HIV-1 transactivator protein induction of suppressor of cytokine signaling-2 contributes to dysregulation of IFN{gamma} signaling.
AuthorsCheng SM, Li JC, Lin SS, Lee DC, Liu L, Chen Z, Lau AS,
JournalBlood
PubMed ID19279332
HIV infection remains a worldwide threat. HIV-1 transactivator protein Tat is one of the retroviral proteins identified as a key immunomodulator in AIDS pathogenesis. Although the primary function of Tat is to regulate HIV-1 replication in the infected cell, it also dysregulates cytokine production resulting in perturbation of the host ... More
eIF4E activation is commonly elevated in advanced human prostate cancers and significantly related to reduced patient survival.
AuthorsGraff JR, Konicek BW, Lynch RL, Dumstorf CA, Dowless MS, McNulty AM, Parsons SH, Brail LH, Colligan BM, Koop JW, Hurst BM, Deddens JA, Neubauer BL, Stancato LF, Carter HW, Douglass LE, Carter JH,
JournalCancer Res
PubMed ID19383915
Elevated eukaryotic translation initiation factor 4E (eIF4E) function induces malignancy in experimental models by selectively enhancing translation of key malignancy-related mRNAs (c-myc and BCL-2). eIF4E activation may reflect increased eIF4E expression or phosphorylation of its inhibitory binding proteins (4E-BP). By immunohistochemical analyses of 148 tissues from 89 prostate cancer patients, ... More
Complex N-glycan and metabolic control in tumor cells.
AuthorsMendelsohn R, Cheung P, Berger L, Partridge E, Lau K, Datti A, Pawling J, Dennis JW,
JournalCancer Res
PubMed ID17942907
Golgi beta1,6N-acetylglucosaminyltransferase V (Mgat5) produces beta1,6GlcNAc-branched complex N-glycans on cell surface glycoproteins that bind to galectins and promote surface residency of glycoproteins, including cytokine receptors. Carcinoma cells from polyomavirus middle T (PyMT) transgenic mice on a Mgat5-/- background have reduced surface levels of epidermal growth factor (EGF) and transforming growth ... More
Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation.
AuthorsJoshi B, Bastiani M, Strugnell SS, Boscher C, Parton RG, Nabi IR,
JournalJ Cell Biol
PubMed ID23091071
'Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase-dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In ... More
Identification of novel small molecule inhibitors of centrosome clustering in cancer cells.
AuthorsKawamura E, Fielding AB, Kannan N, Balgi A, Eaves CJ, Roberge M, Dedhar S,
Journal
PubMed ID24091544
'Most normal cells have two centrosomes that form bipolar spindles during mitosis, while cancer cells often contain more than two, or '
Engagement of the ATR-dependent DNA damage response at the human papillomavirus 18 replication centers during the initial amplification.
AuthorsReinson T, Toots M, Kadaja M, Pipitch R, Allik M, Ustav E, Ustav M,
JournalJ Virol
PubMed ID23135710
'We have previously demonstrated that the human papillomavirus (HPV) genome replicates effectively in U2OS cells after transfection using electroporation. The transient extrachromosomal replication, stable maintenance, and late amplification of the viral genome could be studied for high- and low-risk mucosal and cutaneous papillomaviruses. Recent findings indicate that the cellular DNA ... More
alpha2HS-glycoprotein, an antagonist of transforming growth factor beta in vivo, inhibits intestinal tumor progression.
AuthorsSwallow CJ, Partridge EA, Macmillan JC, Tajirian T, DiGuglielmo GM, Hay K, Szweras M, Jahnen-Dechent W, Wrana JL, Redston M, Gallinger S, Dennis JW,
JournalCancer Res
PubMed ID15374947
'Transforming growth factor (TGF)-beta1 is associated with tumor progression and resistance to chemotherapy in established cancers, as well as host immune suppression. Here, we show that the serum glycoprotein alpha2-HS-glycoprotein (AHSG) blocks TGF-beta1 binding to cell surface receptors, suppresses TGF-beta signal transduction, and inhibits TGF-beta-induced epithelial-mesenchymal transition, suggesting that AHSG ... More
Identification of a nonkinase target mediating cytotoxicity of novel kinase inhibitors.
AuthorsRoss-Macdonald P, de Silva H, Guo Q, Xiao H, Hung CY, Penhallow B, Markwalder J, He L, Attar RM, Lin TA, Seitz S, Tilford C, Wardwell-Swanson J, Jackson D,
JournalMol Cancer Ther
PubMed ID19001433
'In developing inhibitors of the LIM kinases, the initial lead molecules combined potent target inhibition with potent cytotoxic activity. However, as subsequent compounds were evaluated, the cytotoxic activity separated from inhibition of LIM kinases. A rapid determination of the cytotoxic mechanism and its molecular target was enabled by integrating data ... More
AAK1 identified as an inhibitor of neuregulin-1/ErbB4-dependent neurotrophic factor signaling using integrative chemical genomics and proteomics.
AuthorsKuai L, Ong SE, Madison JM, Wang X, Duvall JR, Lewis TA, Luce CJ, Conner SD, Pearlman DA, Wood JL, Schreiber SL, Carr SA, Scolnick EM, Haggarty SJ,
JournalChem Biol
PubMed ID21802010
'Target identification remains challenging for the field of chemical biology. We describe an integrative chemical genomic and proteomic approach combining the use of differentially active analogs of small molecule probes with stable isotope labeling by amino acids in cell culture-mediated affinity enrichment, followed by subsequent testing of candidate targets using ... More
The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model.
'Aurora kinases play key roles in regulating centrosome maturation, mitotic spindle formation, and cytokinesis during cell division, and are considered promising drug targets due to their frequent overexpression in a variety of human cancers. SNS-314 is a selective and potent pan Aurora inhibitor currently in a dose escalation phase 1 ... More
Simvastatin induces apoptosis in human breast cancer cells in a NFkappaB-dependent manner and abolishes the anti-apoptotic signaling of TF/FVIIa and TF/FVIIa/FXa.
AuthorsAberg M, Wickström M, Siegbahn A,
JournalThromb Res
PubMed ID18031796
'Statins have benefits independent of the plasma cholesterol properties among cancer patients and tissue factor (TF)/FVIIa induce PI3-kinase/AKT dependent anti-apoptosis during serum starvation. We analyzed how simvastatin induces apoptosis in human breast cancer cells and the influence of FVIIa and/or FXa on the proposed apoptosis. MDA-MB-231 cells were serum starved ... More
Retinoic acid evoked-differentiation of neuroblastoma cells predominates over growth factor stimulation: an automated image capture and quantitation approach to neuritogenesis.
AuthorsSimpson PB, Bacha JI, Palfreyman EL, Woollacott AJ, McKernan RM, Kerby J
JournalAnal Biochem
PubMed ID11757502
'To facilitate the characterization of compounds that have positive growth factor mimetic effects on neuritogenesis, we have implemented a high-throughput functional assay which measures, in a multiparametric manner, the proliferation and differentiation characteristics of cells in a microtiter plate. Conditions were established using chronic incubation of SH-SY5Y human neuroblastoma cells ... More
Chemotherapeutic drugs and human tumor cells cytokine network.
AuthorsLevina V, Su Y, Nolen B, Liu X, Gordin Y, Lee M, Lokshin A, Gorelik E
JournalInt J Cancer
PubMed ID18697197
'The ability of human tumor cell lines to produce various cytokines, chemokines, angiogenic and growth factors was investigated using Luminex multiplex technology. Media conditioned by tumor cells protected tumor cells from drug-induced apoptosis and stimulated tumor cell proliferation. Antibodies neutralizing IL-6, CXCL8, CCL2 and CCL5 blocked this stimulation. Treatment of ... More
Philinopside E, a new sulfated saponin from sea cucumber, blocks the interaction between kinase insert domain-containing receptor (KDR) and alphavbeta3 integrin via binding to the extracellular domain of KDR.
AuthorsTian F, Zhu CH, Zhang XW, Xie X, Xin XL, Yi YH, Lin LP, Geng MY, Ding J,
JournalMol Pharmacol
PubMed ID17565003
'Vascular endothelial growth factor (VEGF) signaling pathway is essential for tumor angiogenesis and has long been recognized as a promising target for cancer therapy. Current view holds that physical interaction between alpha(v)beta(3) integrin and kinase insert domain-containing receptor (KDR) is important in regulating angiogenesis and tumor development. We have reported ... More
Antiangiogenic activity of 2-deoxy-D-glucose.
AuthorsMerchan JR, Kovács K, Railsback JW, Kurtoglu M, Jing Y, Piña Y, Gao N, Murray TG, Lehrman MA, Lampidis TJ,
JournalPLoS One
PubMed ID21060881
'During tumor angiogenesis, endothelial cells (ECs) are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on in vitro and in vivo angiogenesis ... More
RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini.
AuthorsGonzalez-Suarez E, Branstetter D, Armstrong A, Dinh H, Blumberg H, Dougall WC,
JournalMol Cell Biol
PubMed ID17145767
'RANK and RANKL, the key regulators of osteoclast differentiation and activation, also play an important role in the control of proliferation and differentiation of mammary epithelial cells during pregnancy. Here, we show that RANK protein expression is strictly regulated in a spatial and temporal manner during mammary gland development. RANK ... More
Chemical enhancers of cytokine signaling that suppress microfilament turnover and tumor cell growth.
AuthorsPark HJ, Partridge E, Cheung P, Pawling J, Donovan R, Wrana JL, Dennis JW,
JournalCancer Res
PubMed ID16585180
'The transforming growth factor-beta (TGF-beta) family of cytokines regulates cell proliferation, morphogenesis, and specialized cell functions in metazoans. Herein, we screened a compound library for modifiers of TGF-beta signaling in NMuMG epithelial cells using a cell-based assay to measure Smad2/3 nuclear translocation. We identified five enhancers of TGF-beta signaling that ... More
Tesaglitazar, a dual PPAR-a/? agonist, hamster carcinogenicity, investigative animal and clinical studies.
AuthorsLindblom P, Berg AL, Zhang H, Westerberg R, Tugwood J, Lundgren H, Marcusson-Ståhl M, Sjögren N, Blomgren B, Öhman P, Skånberg I, Evans J, Hellmold H
JournalToxicol Pathol
PubMed ID22131108
'Tesaglitazar was developed as a dual peroxisome proliferator-activated receptor (PPARa/?). To support the clinical program, a hamster carcinogenicity study was performed. The only neoplastic findings possibly related to treatment with tesaglitazar were low incidences of hemangioma and hemangiosarcoma in the liver of male animals. A high-power, two-year investigative study with ... More
A kinome-wide siRNA screen identifies multiple roles for protein kinases in hypoxic stress adaptation, including roles for IRAK4 and GAK in protection against apoptosis in VHL-/- renal carcinoma cells, despite activation of the NF-?B pathway.
AuthorsPan J, Zhang J, Hill A, Lapan P, Berasi S, Bates B, Miller C, Haney S,
JournalJ Biomol Screen
PubMed ID23591012
'Hypoxia induces changes to cancer cells that make them more resistant to treatment. We have looked at signaling pathways that facilitate these changes by screening the human kinome for effects on hypoxic responses in SW480 colon cancer cells. Hits identified in the screen were examined for effects on multiple molecular ... More
mTOR-dependent proliferation defect in human ES-derived neural stem cells affected by myotonic dystrophy type 1.
AuthorsDenis JA, Gauthier M, Rachdi L, Aubert S, Giraud-Triboult K, Poydenot P, Benchoua A, Champon B, Maury Y, Baldeschi C, Scharfmann R, Piétu G, Peschanski M, Martinat C,
JournalJ Cell Sci
PubMed ID23444380
'Patients with myotonic dystrophy type 1 exhibit a diversity of symptoms that affect many different organs. Among these are cognitive dysfunctions, the origin of which has remained elusive, partly because of the difficulty in accessing neural cells. Here, we have taken advantage of pluripotent stem cell lines derived from embryos ... More
Molecular characterization of the cytotoxic mechanism of multiwall carbon nanotubes and nano-onions on human skin fibroblast.
'The increasing use of nanotechnology in consumer products and medical applications underlies the importance of understanding its potential toxic effects to people and the environment. Although both fullerene and carbon nanotubes have been demonstrated to accumulate to cytotoxic levels within organs of various animal models and cell types and carbon ... More
AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo.
AuthorsLoddick SA, Ross SJ, Thomason AG, Robinson DM, Walker GE, Dunkley TP, Brave SR, Broadbent N, Stratton NC, Trueman D, Mouchet E, Shaheen FS, Jacobs VN, Cumberbatch M, Wilson J, Jones RD, Bradbury RH, Rabow A, Gaughan L, Womack C, Barry ST, Robson CN, Critchlow SE, Wedge SR, Brooks AN,
Journal
PubMed ID23861347
'Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and ... More
AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer.
AuthorsWedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jürgensmeier JM, Ogilvie DJ,
JournalCancer Res
PubMed ID15899831
'Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a promising therapeutic approach that aims to stabilize the progression of solid malignancies by abrogating tumor-induced angiogenesis. This may be accomplished by inhibiting the kinase activity of VEGF receptor-2 (KDR), which has a key role in mediating VEGF-induced responses. The novel ... More
Identification of a novel function for the chromatin remodeling protein ING2 in muscle differentiation.
AuthorsEapen SA, Netherton SJ, Sarker KP, Deng L, Chan A, Riabowol K, Bonni S,
JournalPLoS One
PubMed ID22808232
'The inhibitor of growth (ING) family of zinc-finger plant homeodomain (PHD)-containing chromatin remodeling protein controls gene expression and has been implicated in the regulation of cell proliferation and death. However, the role of ING proteins in cell differentiation remains largely unexplored. Here, we identify an essential function for ING2 in ... More
A novel function for Cyclin A2: control of cell invasion via RhoA signaling.
AuthorsArsic N, Bendris N, Peter M, Begon-Pescia C, Rebouissou C, Gadéa G, Bouquier N, Bibeau F, Lemmers B, Blanchard JM,
JournalJ Cell Biol
PubMed ID22232705
'Cyclin A2 plays a key role in cell cycle regulation. It is essential in embryonic cells and in the hematopoietic lineage yet dispensable in fibroblasts. In this paper, we demonstrate that Cyclin A2-depleted cells display a cortical distribution of actin filaments and increased migration. These defects are rescued by restoration ... More
Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor.
AuthorsNoren NK, Yang NY, Silldorff M, Mutyala R, Pasquale EB,
JournalBiochem J
PubMed ID19552627
'Receptor tyrosine kinases of the Eph family become tyrosine phosphorylated and initiate signalling events upon binding of their ligands, the ephrins. Eph receptors such as EphA2 and EphB4 are highly expressed but poorly tyrosine phosphorylated in many types of cancer cells, suggesting a limited interaction with ephrin ligands. Nevertheless, decreasing ... More
The antisignaling agent SC-alpha alpha delta 9, 4-(benzyl-(2-[(2,5-diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)- 2-decanoylaminobutyric acid, is a structurally unique phospholipid analogue with phospholipase C inhibitory activity.
AuthorsVogt A, Pestell KE, Day BW, Lazo JS, Wipf P,
JournalMol Cancer Ther
PubMed ID12481409
'Phospholipids and lipid second messengers mediate mitogenic signal transduction and oncogenesis, but there have been few successful examples of small molecules that affect biologically important phospholipid metabolism. Here we investigated the actions of a previously described antitumor agent, 4-(benzyl-(2-[(2,5-diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)- 2-decanoylaminobutyric acid (SC-alpha alpha delta 9), which has antisignaling properties, on ... More
Angiogenic potential of 3-nitro-4-hydroxy benzene arsonic acid (roxarsone).
AuthorsBasu P, Ghosh RN, Grove LE, Klei L, Barchowsky A,
JournalEnviron Health Perspect
PubMed ID18414637
'Roxarsone (3-nitro-4-hydroxy benzene arsonic acid) is an arsenic compound widely used in the poultry industry as a feed additive to prevent coccidiosis, stimulate growth, and to improve tissue pigmentation. Little is known about the potential human health effects from roxarsone released into the environment from chicken waste or from residual ... More
Mechanistic insights into achievement of cardiac allograft long-term survival by treatment with immature dendritic cells and sub-dose sirolimus.
AuthorsTao R, Wang L, Chen CH, Wang SH, Demarco RA, Lotze MT, Thai NL, Fung JJ, Lu L, Qian S,
JournalJ Heart Lung Transplant
PubMed ID16507425
'Administration of immature dendritic cells (DC) prolongs but does not result in indefinite allograft survival. We attempted to achieve this goal by adding a sub-therapeutic dose of immunosuppression. DC propagated from B10 (H-2(b)) mouse bone marrow (BM) were transfected with nuclear factor-kappaB (NF-kappaB)-binding-site-specific oligodeoxyribonucleotide (ODN). The allostimulatory activity of transfected ... More
Inflammatory pathway analysis using a high content screening platform.
AuthorsBertelsen M, Sanfridson A,
JournalAssay Drug Dev Technol
PubMed ID15971988
'High content cellular screening assays are useful tools to investigate the interplay between signaling pathways and offer valuable platforms to determine the mode of action, potency, and selectivity of potential drug candidates in a biological setting. We describe a cell-based multiplex fluorescent imaging assay that permits concurrent detection and quantification ... More
Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection.
AuthorsRenna M, Schaffner C, Brown K, Shang S, Tamayo MH, Hegyi K, Grimsey NJ, Cusens D, Coulter S, Cooper J, Bowden AR, Newton SM, Kampmann B, Helm J, Jones A, Haworth CS, Basaraba RJ, DeGroote MA, Ordway DJ, Rubinsztein DC, Floto RA,
JournalJ Clin Invest
PubMed ID21804191
'Azithromycin is a potent macrolide antibiotic with poorly understood antiinflammatory properties. Long-term use of azithromycin in patients with chronic inflammatory lung diseases, such as cystic fibrosis (CF), results in improved outcomes. Paradoxically, a recent study reported that azithromycin use in patients with CF is associated with increased infection with nontuberculous ... More
Antitumor effect of novel HSP90 inhibitor NVP-AUY922 against oral squamous cell carcinoma.
AuthorsOkui T, Shimo T, Hassan NM, Fukazawa T, Kurio N, Takaoka M, Naomoto Y, Sasaki A,
JournalAnticancer Res
PubMed ID21508365
'Heat-shock protein 90 (HSP90) is a major cellular chaperone protein. HSP90 supports the correct conformation, stabilization, activation, and localization of ''client'' oncoproteins, many of which are involved in tumor progression. Therefore, the use of HSP90 inhibitors has become a new strategy in antitumor therapy. However, the effects of an HSP90 ... More
PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy.
'The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. Aurora1 and Aurora2 play important but distinct roles in the G(2) and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 ... More
Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.
'The class I phosphatidylinositol 3'' kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting this pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. This study sought ... More
Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells.
AuthorsJanssen A, Kops GJ, Medema RH,
JournalProc Natl Acad Sci U S A
PubMed ID19855003
'The mitotic checkpoint has evolved to prevent chromosome mis-segregations by delaying mitosis when unattached chromosomes are present. Inducing severe chromosome segregation errors by ablating the mitotic checkpoint causes cell death. Here we have analyzed the consequences of gradual increases in chromosome segregation errors on the viability of tumor cells and ... More
Identifying a resistance determinant for the antimitotic natural products disorazole C1 and A1.
AuthorsLazo JS, Reese CE, Vogt A, Vollmer LL, Kitchens CA, Günther E, Graham TH, Hopkins CD, Wipf P,
JournalJ Pharmacol Exp Ther
PubMed ID20008956
'Disorazoles are macrocyclic polyketides first isolated from the fermentation broth of the myxobacterium Sorangium cellulosum. Both the major fermentation product disorazole A(1) and its much rarer companion disorazole C(1) exhibit potent cytotoxic activity against many human tumor cells. Furthermore, the disorazoles appear to bind tubulin uniquely among known antimitotic agents, ... More
Novel tight-binding inhibitory factor-kappaB kinase (IKK-2) inhibitors demonstrate target-specific anti-inflammatory activities in cellular assays and following oral and local delivery in an in vivo model of airway inflammation.
AuthorsSommers CD, Thompson JM, Guzova JA, Bonar SL, Rader RK, Mathialagan S, Venkatraman N, Holway VW, Kahn LE, Hu G, Garner DS, Huang HC, Chiang PC, Schindler JF, Hu Y, Meyer DM, Kishore NN,
JournalJ Pharmacol Exp Ther
PubMed ID19478133
'Nuclear factor-kappaB (NF-kappaB) is one of the major families of transcription factors activated during the inflammatory response in asthma and chronic obstructive pulmonary disease. Inhibitory factor-kappaB kinase 2 (IKK-2) has been shown to play a pivotal role in cytokine-induced NF-kappaB activation in airway epithelium and in disease-relevant cells. Nevertheless, the ... More
Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells.
AuthorsAlbert BJ, McPherson PA, O'Brien K, Czaicki NL, Destefino V, Osman S, Li M, Day BW, Grabowski PJ, Moore MJ, Vogt A, Koide K,
JournalMol Cancer Ther
PubMed ID19671752
'FR901464 is a potent antitumor natural product that binds to the splicing factor 3b complex and inhibits pre-mRNA splicing. Its analogue, meayamycin, is two orders of magnitude more potent as an antiproliferative agent against human breast cancer MCF-7 cells. Here, we report the picomolar antiproliferative activity of meayamycin against various ... More
Biological significance of prolactin in gynecologic cancers.
AuthorsLevina VV, Nolen B, Su Y, Godwin AK, Fishman D, Liu J, Mor G, Maxwell LG, Herberman RB, Szczepanski MJ, Szajnik ME, Gorelik E, Lokshin AE,
JournalCancer Res
PubMed ID19491263
'There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, ... More
The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures.
AuthorsHowes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT,
JournalMol Cancer Ther
PubMed ID17766839
'The phosphatidylinositol 3-kinase (PI3K) pathway is activated in many human tumors and mediates processes such as cell proliferation, survival, adhesion, and motility. The natural product, wortmannin, has been widely used to study the functional consequences of PI3K inhibition in both normal and transformed cells in culture but is not a ... More
Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.
AuthorsLiu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C,
JournalCancer Res
PubMed ID17178882
'Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC). Sorafenib (BAY 43-9006, Nexavar) is a multikinase inhibitor with activity against Raf kinase and several receptor tyrosine kinases, including vascular endothelial growth factor ... More
Cellular effect of high doses of silica-coated quantum dot profiled with high throughput gene expression analysis and high content cellomics measurements.
'Quantum dots (Qdots) are now used extensively for labeling in biomedical research, and this use is predicted to grow because of their many advantages over alternative labeling methods. Uncoated Qdots made of core/shell CdSe/ZnS are toxic to cells because of the release of Cd2+ ions into the cellular environment. This ... More
PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity.
AuthorsSoncini C, Carpinelli P, Gianellini L, Fancelli D, Vianello P, Rusconi L, Storici P, Zugnoni P, Pesenti E, Croci V, Ceruti R, Giorgini ML, Cappella P, Ballinari D, Sola F, Varasi M, Bravo R, Moll J,
JournalClin Cancer Res
PubMed ID16818708
'Aurora kinases play critical roles during mitosis in chromosome segregation and cell division. The aim of this study was to determine the preclinical profile of a novel, highly selective Aurora kinase inhibitor, PHA-680632, as a candidate for anticancer therapy. The activity of PHA-680632 was assayed in a biochemical ATP competitive ... More
The immunosuppressant cyclosporin A antagonizes human formyl peptide receptor through inhibition of cognate ligand binding.
AuthorsYan P, Nanamori M, Sun M, Zhou C, Cheng N, Li N, Zheng W, Xiao L, Xie X, Ye RD, Wang MW,
JournalJ Immunol
PubMed ID17082621
'Cyclosporin A (CsA) is a fungus-derived cyclic undecapeptide with potent immunosuppressive activity. Its analog, cyclosporin H (CsH), lacks immunosuppressive function but can act as an antagonist for the human formyl peptide receptor (FPR). More recent studies have shown that CsA also inhibits fMLF-induced degranulation in differentiated HL-60 promyelocytic leukemia cells. ... More
Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model.
AuthorsFryknäs M, Rickardson L, Wickström M, Dhar S, Lövborg H, Gullbo J, Nygren P, Gustafsson MG, Isaksson A, Larsson R,
JournalJ Biomol Screen
PubMed ID16928983
'The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective ... More
The ubiquitin-conjugating enzyme E2-EPF is overexpressed in primary breast cancer and modulates sensitivity to topoisomerase II inhibition.
'We identified the ubiquitin-conjugating enzyme E2-EPF mRNA as differentially expressed in breast tumors relative to normal tissues and performed studies to elucidate its putative role in cancer. We demonstrated that overexpression of E2-EPF protein correlated with estrogen receptor (ER) negativity in breast cancer specimens and that its expression is cell ... More
RNAi screening reveals requirement for host cell secretory pathway in infection by diverse families of negative-strand RNA viruses.
AuthorsPanda D, Das A, Dinh PX, Subramaniam S, Nayak D, Barrows NJ, Pearson JL, Thompson J, Kelly DL, Ladunga I, Pattnaik AK,
JournalProc Natl Acad Sci U S A
PubMed ID22065774
'Negative-strand (NS) RNA viruses comprise many pathogens that cause serious diseases in humans and animals. Despite their clinical importance, little is known about the host factors required for their infection. Using vesicular stomatitis virus (VSV), a prototypic NS RNA virus in the family Rhabdoviridae, we conducted a human genome-wide siRNA ... More
AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.
AuthorsChresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, Vincent JP, Ellston R, Jones D, Sini P, James D, Howard Z, Dudley P, Hughes G, Smith L, Maguire S, Hummersone M, Malagu K, Menear K, Jenkins R, Jacobsen M, Smith GC, Guichard S, Pass M,
JournalCancer Res
PubMed ID20028854
'The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we ... More
Small interfering RNA library screen of human kinases and phosphatases identifies polo-like kinase 1 as a promising new target for the treatment of pediatric rhabdomyosarcomas.
AuthorsHu K, Lee C, Qiu D, Fotovati A, Davies A, Abu-Ali S, Wai D, Lawlor ER, Triche TJ, Pallen CJ, Dunn SE,
JournalMol Cancer Ther
PubMed ID19887553
'Rhabdomyosarcoma, consisting of alveolar (aRMS) and embryonal (eRMS) subtypes, is the most common type of sarcoma in children. Currently, there are no targeted drug therapies available for rhabdomyosarcoma. In searching for new molecular therapeutic targets, we carried out genome-wide small interfering RNA (siRNA) library screens targeting human phosphatases (n = ... More
The Zfx gene is expressed in human gliomas and is important in the proliferation and apoptosis of the human malignant glioma cell line U251.
AuthorsZhou Y, Su Z, Huang Y, Sun T, Chen S, Wu T, Chen G, Xie X, Li B, Du Z,
JournalJ Exp Clin Cancer Res
PubMed ID22185393
'Zfx is a zinc finger protein of the Zfy family, whose members are highly conserved in vertebrates. Zfx is a shared transcriptional regulator of both embryonic stem cells (ESC) and hematopoietic stem cells (HSC), which suggests a common genetic basis of self-renewal in embryonic and adult stem cells. The level ... More
A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil.
AuthorsJesus AA, Osman M, Silva CA, Kim PW, Pham TH, Gadina M, Yang B, Bertola DR, Carneiro-Sampaio M, Ferguson PJ, Renshaw BR, Schooley K, Brown M, Al-Dosari A, Al-Alami J, Sims JE, Goldbach-Mansky R, El-Shanti H,
JournalArthritis Rheum
PubMed ID22127713
'Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: ... More
Single cell cytometry of protein function in RNAi treated cells and in native populations.
AuthorsLaPan P, Zhang J, Pan J, Hill A, Haney SA,
JournalBMC Cell Biol
PubMed ID18673568
'High Content Screening has been shown to improve results of RNAi and other perturbations, however significant intra-sample heterogeneity is common and can complicate some analyses. Single cell cytometry can extract important information from subpopulations within these samples. Such approaches are important for immune cells analyzed by flow cytometry, but have ... More
Functional genomics identifies ABCC3 as a mediator of taxane resistance in HER2-amplified breast cancer.
AuthorsO'Brien C, Cavet G, Pandita A, Hu X, Haydu L, Mohan S, Toy K, Rivers CS, Modrusan Z, Amler LC, Lackner MR,
JournalCancer Res
PubMed ID18593940
'Breast cancer is a heterogeneous disease with distinct molecular subtypes characterized by differential response to targeted and chemotherapeutic agents. Enhanced understanding of the genetic alterations characteristic of different subtypes is needed to pave the way for more personalized administration of therapeutic agents. We have taken a functional genomics approach using ... More
Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714.
AuthorsFeng B, Xu JJ, Bi YA, Mireles R, Davidson R, Duignan DB, Campbell S, Kostrubsky VE, Dunn MC, Smith AR, Wang HF,
JournalToxicol Sci
PubMed ID19223659
'CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clinical development due to unexpected hepatotoxicity in cancer patients. Based on the clinical manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition ... More
Multiparametric evaluation of apoptosis: effects of standard cytotoxic agents and the cyanoguanidine CHS 828.
AuthorsLövborg H, Nygren P, Larsson R
JournalMol Cancer Ther
PubMed ID15141009
'A multiparametric high-content screening assay for measurement of apoptosis was developed. HeLa cells and lymphoma U-937 cells were exposed to cytotoxic drugs in flat-bottomed optical microtiter plates. After incubation, the DNA-binding dye Hoechst 33342, fluorescein-tagged probes that covalently bind active caspases and chloromethyl-X-rosamine to detect mitochondrial membrane potential (MMP) were ... More
Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress.
'Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We ... More
Pandemic H1N1 Influenza Infection and Vaccination in Humans Induces Cross-Protective Antibodies that Target the Hemagglutinin Stem.
AuthorsThomson CA, Wang Y, Jackson LM, Olson M, Wang W, Liavonchanka A, Keleta L, Silva V, Diederich S, Jones RB, Gubbay J, Pasick J, Petric M, Jean F, Allen VG, Brown EG, Rini JM, Schrader JW,
JournalFront Immunol
PubMed ID22586427
'Most monoclonal antibodies (mAbs) generated from humans infected or vaccinated with the 2009 pandemic H1N1 (pdmH1N1) influenza virus targeted the hemagglutinin (HA) stem. These anti-HA stem mAbs mostly used IGHV1-69 and bound readily to epitopes on the conventional seasonal influenza and pdmH1N1 vaccines. The anti-HA stem mAbs neutralized pdmH1N1, seasonal ... More
In vitro and in vivo anti-inflammatory activities of columbin through the inhibition of cycloxygenase-2 and nitric oxide but not the suppression of NF-?B translocation.
AuthorsIbrahim Abdelwahab S, Syaed Koko W, Mohamed Elhassan Taha M, Mohan S, Achoui M, Ameen Abdulla M, Rais Mustafa M, Ahmad S, Ibrahim Noordin M, Lip Yong C, Roslan Sulaiman M, Othman R, Amir Hassan A,
JournalEur J Pharmacol
PubMed ID22227329
'Columbin, a diterpenoid furanolactone, was isolated purely for the first time from the plant species Tinspora bakis. The anti-inflammatory effects of columbin were studied in vitro, in silico and in vivo. The effect of columbin on nitric oxide was examined on lipopolysaccharide-interferon-gamma (LPS/IFN) induced RAW264.7 macrophages. In vitro and in ... More
Curcumin inhibits lung cancer cell invasion and metastasis through the tumor suppressor HLJ1.
AuthorsChen HW, Lee JY, Huang JY, Wang CC, Chen WJ, Su SF, Huang CW, Ho CC, Chen JJ, Tsai MF, Yu SL, Yang PC,
JournalCancer Res
PubMed ID18794131
'Curcumin (diferuloylmethane) is an active component of the spice turmeric and has a diversity of antitumor activities. In this study, we found that curcumin can inhibit cancer cell invasion and metastasis through activation of the tumor suppressor DnaJ-like heat shock protein 40 (HLJ1). Human lung adenocarcinoma cells (CL1-5) treated with ... More
Mineralocorticoid and glucocorticoid receptors differentially regulate NF-kappaB activity and pro-inflammatory cytokine production in murine BV-2 microglial cells.
AuthorsChantong B, Kratschmar DV, Nashev LG, Balazs Z, Odermatt A,
JournalJ Neuroinflammation
PubMed ID23190711
'Microglia, the resident macrophage-like cells in the brain, regulate innate immune responses in the CNS to protect neurons. However, excessive activation of microglia contributes to neurodegenerative diseases. Corticosteroids are potent modulators of inflammation and mediate their effects by binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Here, the coordinated ... More
Humoral immunity to smallpox vaccines and monkeypox virus challenge: proteomic assessment and clinical correlations.
'Despite the eradication of smallpox, orthopoxviruses (OPV) remain public health concerns. Efforts to develop new therapeutics and vaccines for smallpox continue through their evaluation in animal models despite limited understanding of the specific correlates of protective immunity. Recent monkeypox virus challenge studies have established the black-tailed prairie dog (Cynomys ludovicianus) ... More
Micronutrient modulation of NF-?B in oral keratinocytes exposed to periodontal bacteria.
AuthorsMilward MR, Chapple IL, Carter K, Matthews JB, Cooper PR,
JournalInnate Immun
PubMed ID22890546
'Chronic periodontal diseases are characterised by a dysregulated and exaggerated inflammatory/immune response to plaque bacteria. We have demonstrated previously that oral keratinocytes up-regulate key molecular markers of inflammation, including NF-?B and cytokine signalling, when exposed to the periodontal bacteria Porphyromonas gingivalis and Fusobacterium nucleatum in vitro. The purpose of the current ... More
The role of sphingosine-1-phosphate transporter Spns2 in immune system function.
AuthorsNijnik A, Clare S, Hale C, Chen J, Raisen C, Mottram L, Lucas M, Estabel J, Ryder E, Adissu H, Adams NC, Ramirez-Solis R, White JK, Steel KP, Dougan G, Hancock RE,
JournalJ Immunol
PubMed ID22664872
'Sphingosine-1-phosphate (S1P) is lipid messenger involved in the regulation of embryonic development, immune system functions, and many other physiological processes. However, the mechanisms of S1P transport across cellular membranes remain poorly understood, with several ATP-binding cassette family members and the spinster 2 (Spns2) member of the major facilitator superfamily known ... More
Immunological and nonimmunological effects of indoleamine 2,3-dioxygenase on breast tumor growth and spontaneous metastasis formation.
AuthorsLevina V, Su Y, Gorelik E,
JournalClin Dev Immunol
PubMed ID22654951
'The role of the tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO1), in tumor escape and metastasis formation was analyzed using two pairs of Ido1+ and Ido1- murine breast cancer cell lines. Ido1 expression in 4T1 cells was knocked down by shRNA, and Ido1 expression in NT-5 cells was upregulated by stable transfection. ... More
AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies.
AuthorsZabludoff SD, Deng C, Grondine MR, Sheehy AM, Ashwell S, Caleb BL, Green S, Haye HR, Horn CL, Janetka JW, Liu D, Mouchet E, Ready S, Rosenthal JL, Queva C, Schwartz GK, Taylor KJ, Tse AN, Walker GE, White AM,
JournalMol Cancer Ther
PubMed ID18790776
'Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in ... More
Early appearance of neutralizing immunoglobulin G3 antibodies is associated with chikungunya virus clearance and long-term clinical protection.
AuthorsKam YW, Simarmata D, Chow A, Her Z, Teng TS, Ong EK, Rénia L, Leo YS, Ng LF,
JournalJ Infect Dis
PubMed ID22389226
'Chikungunya virus (CHIKV) and related arboviruses have been responsible for large epidemic outbreaks with serious economic and social impact. Although infected individuals clear the virus from the blood, some develop debilitating and prolonged arthralgia. We investigated specificity and strength of antibody responses in a longitudinal study on CHIKV-infected patients and ... More
NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies.
AuthorsValsasina B, Beria I, Alli C, Alzani R, Avanzi N, Ballinari D, Cappella P, Caruso M, Casolaro A, Ciavolella A, Cucchi U, De Ponti A, Felder E, Fiorentini F, Galvani A, Gianellini LM, Giorgini ML, Isacchi A, Lansen J, Pesenti E, Rizzi S, Rocchetti M, Sola F, Moll J,
JournalMol Cancer Ther
PubMed ID22319201
'Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor ... More
Essential role of TAK1 in regulating mantle cell lymphoma survival.
'TGF-ß-activated kinase 1 (TAK1), a member of the MAPK kinase family, plays a key role in B-cell growth and development. In the present study, we examined the potential role of TAK1 as a therapeutic target for lymphoma. Here, we show that the active phosphorylated form of TAK1 is abundantly expressed ... More
Kinome-wide functional genomics screen reveals a novel mechanism of TNFa-induced nuclear accumulation of the HIF-1a transcription factor in cancer cells.
AuthorsSchoolmeesters A, Brown DD, Fedorov Y,
JournalPLoS One
PubMed ID22355351
'Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1a, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1a activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. ... More
High-content imaging characterization of cell cycle therapeutics through in vitro and in vivo subpopulation analysis.
'Although the cycling of eukaryotic cells has long been a primary focus for cancer therapeutics, recent advances in imaging and data analysis allow even further definition of cellular events as they occur in individual cells and cellular subpopulations in response to treatment. High-content imaging (HCI) has been an effective tool ... More
AuthorsKaltenbach LS, Bolton MM, Shah B, Kanju PM, Lewis GM, Turmel GJ, Whaley JC, Trask OJ, Lo DC,
JournalJ Biomol Screen
PubMed ID20581077
'Huntington''s disease (HD) is a fatal neurodegenerative disease characterized by progressive cognitive, behavioral, and motor deficits and caused by expansion of a polyglutamine repeat in the Huntingtin protein (Htt). Despite its monogenic nature, HD pathogenesis includes obligatory non-cell-autonomous pathways involving both the cortex and the striatum, and therefore effective recapitulation ... More
Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer.
AuthorsRamsay AG, Clear AJ, Fatah R, Gribben JG,
JournalBlood
PubMed ID22547582
'Cancer immune evasion is an emerging hallmark of disease progression. We have demonstrated previously that impaired actin polymerization at the T-cell immunologic synapse is a global immune dysfunction in chronic lymphocytic leukemia (CLL). Direct contact with tumor cells induces defective actin polarization at the synapse in previously healthy T cells, ... More
Structure-activity analysis of niclosamide reveals potential role for cytoplasmic pH in control of mammalian target of rapamycin complex 1 (mTORC1) signaling.
AuthorsFonseca BD, Diering GH, Bidinosti MA, Dalal K, Alain T, Balgi AD, Forestieri R, Nodwell M, Rajadurai CV, Gunaratnam C, Tee AR, Duong F, Andersen RJ, Orlowski J, Numata M, Sonenberg N, Roberge M,
JournalJ Biol Chem
PubMed ID22474287
'Mammalian target of rapamycin complex 1 (mTORC1) signaling is frequently dysregulated in cancer. Inhibition of mTORC1 is thus regarded as a promising strategy in the treatment of tumors with elevated mTORC1 activity. We have recently identified niclosamide (a Food and Drug Administration-approved antihelminthic drug) as an inhibitor of mTORC1 signaling. ... More
Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer.
AuthorsCathcart MC, Gately K, Cummins R, Kay E, O'Byrne KJ, Pidgeon GP,
JournalMol Cancer
PubMed ID21388528
'Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile ... More
Assessment of chemical-induced impairment of human neurite outgrowth by multiparametric live cell imaging in high-density cultures.
AuthorsStiegler NV, Krug AK, Matt F, Leist M,
JournalToxicol Sci
PubMed ID21342877
'Chemicals that specifically alter human neurite outgrowth pose a hazard for the development of the nervous system. The identification of such compounds remains a major challenge, especially in a human test system. To address this issue, we developed an imaging-based procedure in LUHMES human neuronal precursor cells to quantify neurite ... More
YB-1 evokes susceptibility to cancer through cytokinesis failure, mitotic dysfunction and HER2 amplification.
AuthorsDavies AH, Barrett I, Pambid MR, Hu K, Stratford AL, Freeman S, Berquin IM, Pelech S, Hieter P, Maxwell C, Dunn SE,
JournalOncogene
PubMed ID21423216
'Y-box binding protein-1 (YB-1) expression in the mammary gland promotes breast carcinoma that demonstrates a high degree of genomic instability. In the present study, we developed a model of pre-malignancy to characterize the role of this gene during breast cancer initiation and early progression. Antibody microarray technology was used to ... More
Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer.
AuthorsAzzariti A, Bocci G, Porcelli L, Fioravanti A, Sini P, Simone GM, Quatrale AE, Chiarappa P, Mangia A, Sebastian S, Del Bufalo D, Del Tacca M, Paradiso A,
JournalBr J Cancer
PubMed ID21304529
'AZD1152, the prodrug for AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a selective inhibitor of Aurora B kinase activity. Preclinical evaluation of AZD1152 has been reported in several human cancer models. The potentiality of this compound in combination therapy warrants further investigation in solid tumours. This study explored the effects of AZD1152-HQPA ... More
Inhibition of autophagosome formation by the benzoporphyrin derivative verteporfin.
AuthorsDonohue E, Tovey A, Vogl AW, Arns S, Sternberg E, Young RN, Roberge M,
JournalJ Biol Chem
PubMed ID21193398
'Autophagy enables cells to degrade and recycle cytoplasmic materials both as a housekeeping mechanism and in response to extracellular stress such as nutrient deprivation. Recent studies indicate that autophagy also functions as a protective mechanism in response to several cancer therapy agents, making it a prospective therapeutic target. Few pharmacological ... More
Maspin regulates endothelial cell adhesion and migration through an integrin signaling pathway.
AuthorsQin L, Zhang M,
JournalJ Biol Chem
PubMed ID20713357
'Maspin has been identified as a potent angiogenesis inhibitor. However, the molecular mechanism responsible for its anti-angiogenic property is unclear. In this study, we examined the effect of maspin on endothelial cell (EC) adhesion and migration in a cell culture system. We found that maspin was expressed in blood vessels ... More
Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability.
AuthorsLaw JH, Li Y, To K, Wang M, Astanehe A, Lambie K, Dhillon J, Jones SJ, Gleave ME, Eaves CJ, Dunn SE,
JournalPLoS One
PubMed ID20844753
'The Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was highly phosphorylated by ... More
PF-03732010: a fully human monoclonal antibody against P-cadherin with antitumor and antimetastatic activity.
AuthorsZhang CC, Yan Z, Zhang Q, Kuszpit K, Zasadny K, Qiu M, Painter CL, Wong A, Kraynov E, Arango ME, Mehta PP, Popoff I, Casperson GF, Los G, Bender S, Anderes K, Christensen JG, VanArsdale T,
JournalClin Cancer Res
PubMed ID20829331
'P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models. The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic ... More
Expression of G protein-coupled receptor 19 in human lung cancer cells is triggered by entry into S-phase and supports G(2)-M cell-cycle progression.
'It has long been known that G protein-coupled receptors (GPCR) are subject to illegitimate expression in tumor cells. Presumably, hijacking the normal physiologic functions of GPCRs contributes to all biologic capabilities acquired during tumorigenesis. Here, we searched for GPCRs that were expressed in lung cancer: the mRNA encoding orphan G ... More
A photoconvertible fluorescent reporter to track chaperone-mediated autophagy.
AuthorsKoga H, Martinez-Vicente M, Macian F, Verkhusha VV, Cuervo AM,
JournalNat Commun
PubMed ID21750540
'Chaperone-mediated autophagy (CMA) is a selective mechanism for the degradation of soluble proteins in lysosomes. CMA contributes to cellular quality control and is activated as part of the cellular response to different stressors. Defective CMA has been identified in ageing and different age-related diseases. Until now, CMA activity could only ... More
Caspase-3-dependent mitotic checkpoint inactivation by the small-molecule inducers of mitotic slippage SU6656 and geraldol.
AuthorsRiffell JL, Jänicke RU, Roberge M,
JournalMol Cancer Ther
PubMed ID21441410
'Microtubule-targeting cancer drugs such as paclitaxel block cell-cycle progression at mitosis by prolonged activation of the mitotic checkpoint. Cells can spontaneously escape mitotic arrest and enter interphase without chromosome segregation by a process termed mitotic slippage that involves the degradation of cyclin B1 without mitotic checkpoint inactivation. Inducing mitotic slippage ... More
Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents.
AuthorsPeltonen K, Colis L, Liu H, Jäämaa S, Moore HM, Enbäck J, Laakkonen P, Vaahtokari A, Jones RJ, af Hällström TM, Laiho M,
JournalPLoS One
PubMed ID20885994
'Manipulation of the activity of the p53 tumor suppressor pathway has demonstrated potential benefit in preclinical mouse tumor models and has entered human clinical trials. We describe here an improved, extensive small-molecule chemical compound library screen for p53 pathway activation in a human cancer cell line devised to identify hits ... More
Deconstructing the ßcatenin destruction complex: mechanistic roles for the tumor suppressor APC in regulating Wnt signaling.
AuthorsRoberts DM, Pronobis MI, Poulton JS, Waldmann JD, Stephenson EM, Hanna S, Peifer M,
JournalMol Biol Cell
PubMed ID21471006
'Negatively regulating signaling by targeting key effectors for ubiquitination/destruction is essential for development and oncogenesis. The tumor suppressor adenomatous polyposis coli (APC), an essential negative regulator of Wnt signaling, provides a paradigm. APC mutations occur in most colon cancers. Acting in the ' ... More
Quantitative assessment of neurite outgrowth in human embryonic stem cell-derived hN2 cells using automated high-content image analysis.
'Throughout development neurons undergo a number of morphological changes including neurite outgrowth from the cell body. Exposure to neurotoxic chemicals that interfere with this process may result in permanent deficits in nervous system function. Traditionally, rodent primary neural cultures and immortalized human and non-human clonal cell lines have been used ... More
Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase.
AuthorsColombo R, Caldarelli M, Mennecozzi M, Giorgini ML, Sola F, Cappella P, Perrera C, Depaolini SR, Rusconi L, Cucchi U, Avanzi N, Bertrand JA, Bossi RT, Pesenti E, Galvani A, Isacchi A, Colotta F, Donati D, Moll J,
JournalCancer Res
PubMed ID21159646
'MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization ... More
A novel antibody engineering strategy for making monovalent bispecific heterodimeric IgG antibodies by electrostatic steering mechanism.
AuthorsLiu Z, Leng EC, Gunasekaran K, Pentony M, Shen M, Howard M, Stoops J, Manchulenko K, Razinkov V, Liu H, Fanslow W, Hu Z, Sun N, Hasegawa H, Clark R, Foltz IN, Yan W,
Journal
PubMed ID25583986
'Producing pure and well behaved bispecific antibodies (bsAbs) on a large scale for preclinical and clinical testing is a challenging task. Here, we describe a new strategy for making monovalent bispecific heterodimeric IgG antibodies in mammalian cells. We applied an electrostatic steering mechanism to engineer antibody light chain-heavy chain (LC-HC) ... More
Mechanical stress impairs mitosis progression in multi-cellular tumor spheroids.
AuthorsDesmaison A, Frongia C, Grenier K, Ducommun B, Lobjois V,
Journal
PubMed ID24312473
'Growing solid tumors are subjected to mechanical stress that influences their growth rate and development. However, little is known about its effects on tumor cell biology. To explore this issue, we investigated the impact of mechanical confinement on cell proliferation in MultiCellular Tumor Spheroids (MCTS), a 3D culture model that ... More
Human carboxylesterase-2 hydrolyzes the prodrug of gemcitabine (LY2334737) and confers prodrug sensitivity to cancer cells.
'The oral prodrug of gemcitabine LY2334737 is cleaved systemically to gemcitabine; the mechanism responsible for hydrolysis is unknown. LY2334737 cytotoxicity was tested in the NCI-60 panel; mining of microarray expression data identified carboxylesterase (CES) as a top hydrolase candidate. Studies examined whether CES is responsible for hydrolysis and whether cellular ... More
Personalizing the treatment of pediatric medulloblastoma: Polo-like kinase 1 as a molecular target in high-risk children.
AuthorsTriscott J, Lee C, Foster C, Manoranjan B, Pambid MR, Berns R, Fotovati A, Venugopal C, O'Halloran K, Narendran A, Hawkins C, Ramaswamy V, Bouffet E, Taylor MD, Singhal A, Hukin J, Rassekh R, Yip S, Northcott P, Singh SK, Dunham C, Dunn SE,
Journal
PubMed ID24019381
'Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 ... More
ERK2 but not ERK1 mediates HGF-induced motility in non-small cell lung carcinoma cell lines.
AuthorsRadtke S, Milanovic M, Rossé C, De Rycker M, Lachmann S, Hibbert A, Kermorgant S, Parker PJ,
JournalJ Cell Sci
PubMed ID23549785
'Aberrant signalling of receptor tyrosine kinases (RTKs), such as c-Met, the receptor for hepatocyte growth factor (HGF), has been implicated in the oncogenesis of various tumours including non-small cell lung carcinoma (NSCLC). Through its pro-migratory properties, c-Met has been implicated specifically in the process of tumour metastasis, demanding a better ... More
A genome-wide siRNA screen reveals multiple mTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions.
AuthorsLipinski MM, Hoffman G, Ng A, Zhou W, Py BF, Hsu E, Liu X, Eisenberg J, Liu J, Blenis J, Xavier RJ, Yuan J,
JournalDev Cell
PubMed ID20627085
'Autophagy is a cellular catabolic mechanism that plays an essential function in protecting multicellular eukaryotes from neurodegeneration, cancer, and other diseases. However, we still know very little about mechanisms regulating autophagy under normal homeostatic conditions when nutrients are not limiting. In a genome-wide human siRNA screen, we demonstrate that under ... More
Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies.
'Most human mammary epithelial cells (HMEC) cultured from histologically normal breast tissues enter a senescent state termed stasis after 5 to 20 population doublings. These senescent cells display increased size, contain senescence associated beta-galactosidase activity, and express cyclin-dependent kinase inhibitor, p16INK4A (CDKN2A; p16). However, HMEC grown in a serum-free medium, ... More
In vitro and in vivo anticancer activity of (+)-spongistatin 1.
AuthorsXu Q, Huang KC, Tendyke K, Marsh J, Liu J, Qiu D, Littlefield BA, Nomoto K, Atasoylu O, Risatti CA, Sperry JB, Smith AB,
JournalAnticancer Res
PubMed ID21868519
'The marine natural product (+)-spongistatin 1 is an extremely potent growth inhibitory agent having activity against a wide variety of cancer cell lines, while exhibiting low cytotoxicity against quiescent human fibroblasts. Consistent with a microtubule-targeting mechanism of action, (+)-spongistatin 1 causes mitotic arrest in DU145 human prostate cancer cells. More ... More
Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma.
AuthorsSartore-Bianchi A, Gasparri F, Galvani A, Nici L, Darnowski JW, Barbone D, Fennell DA, Gaudino G, Porta C, Mutti L,
JournalClin Cancer Res
PubMed ID17908991
'Purpose of this study has been the assessment of nuclear factor-kappaB (NF-kappaB) as a survival factor in human mesothelial cells (HMC), transformed HMC and malignant mesothelioma (MMe) cells. We aimed at verifying whether the proteasome inhibitor Bortezomib could abrogate NF-kappaB activity in MMe cells, leading to tumor cell death and ... More
A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen.
AuthorsCoppé JP, Patil CK, Rodier F, Krtolica A, Beauséjour CM, Parrinello S, Hodgson JG, Chin K, Desprez PY, Campisi J,
JournalPLoS One
PubMed ID20169192
'Cellular senescence irreversibly arrests cell proliferation in response to oncogenic stimuli. Human cells develop a senescence-associated secretory phenotype (SASP), which increases the secretion of cytokines and other factors that alter the behavior of neighboring cells. We show here that ' ... More
Chloroform Fraction of Centratherum anthelminticum (L.) Seed Inhibits Tumor Necrosis Factor Alpha and Exhibits Pleotropic Bioactivities: Inhibitory Role in Human Tumor Cells.
AuthorsArya A, Achoui M, Cheah SC, Abdelwahab SI, Narrima P, Mohan S, Mustafa MR, Mohd MA,
JournalEvid Based Complement Alternat Med
PubMed ID22474512
'We investigated the antioxidant potential, cytotoxic effect, and TNF-a inhibition activity with NF-?B activation response in a chloroform fraction of Centratherum anthelminticum seeds (CACF). The antioxidant property of CACF was evaluated with DPPH, ORAC, and FRAP assays, which demonstrated significant antioxidant activity. The cytotoxicity of CACF was tested using the ... More
Role of eotaxin-1 signaling in ovarian cancer.
AuthorsLevina V, Nolen BM, Marrangoni AM, Cheng P, Marks JR, Szczepanski MJ, Szajnik ME, Gorelik E, Lokshin AE,
JournalClin Cancer Res
PubMed ID19351767
'Tumor cell growth and migration can be directly regulated by chemokines. In the present study, the association of CCL11 with ovarian cancer has been investigated. Experimental Design and Circulating levels of CCL11 in sera of patients with ovarian cancer were significantly lower than those in healthy women or women with ... More