Medical Specialties Commons^™

Cyclin D1 Silencing Suppresses Tumorigenicity, Impairs Dna Double Strand Break Repair And Thus Radiosensitizes Androgenindependent Prostate Cancer Cells To Dna Damage., F Marampon, G L Gravina, Xiaoming Ju, A Vetuschi, R Sferra, Mathew C Casimiro, S Pompili, C Festuccia, A Colapietro, E Gaudio, E Di Cesare, V Tombolini, Richard Pestell

Department of Cancer Biology Faculty Papers

Patients with hormone-resistant prostate cancer (PCa) have higher biochemical failure rates following radiation therapy (RT). Cyclin D1 deregulated expression in PCa is associated with a more aggressive disease: however its role in radioresistance has not been determined. Cyclin D1 levels in the androgen-independent PC3 and 22Rv1 PCa cells were stably inhibited by infecting with cyclin D1-shRNA. Tumorigenicity and radiosensitivity were investigated using in vitro and in vivo experimental assays. Cyclin D1 silencing interfered with PCa oncogenic phenotype by inducing growth arrest in the G1 phase of cell cycle and reducing soft agar colony formation, migration, invasion in vitro and tumor …

Deletion Of Cyclophilin D Impairs Β-Oxidation And Promotes Glucose Metabolism., Michele Tavecchio, Sofia Lisanti, Michael J Bennett, Lucia R Languino, Dario C Altieri

Department of Cancer Biology Faculty Papers

Cyclophilin D (CypD) is a mitochondrial matrix protein implicated in cell death, but a potential role in bioenergetics is not understood. Here, we show that loss or depletion of CypD in cell lines and mice induces defects in mitochondrial bioenergetics due to impaired fatty acid β-oxidation. In turn, CypD loss triggers a global compensatory shift towards glycolysis, with transcriptional upregulation of effectors of glucose metabolism, increased glucose consumption and higher ATP production. In vivo, the glycolytic shift secondary to CypD deletion is associated with expansion of insulin-producing β-cells, mild hyperinsulinemia, improved glucose tolerance, and resistance to high fat diet-induced liver …

Rac1 P29s Regulates Pd-L1 Expression In Melanoma., Ha Linh Vu, Sheera Rosenbaum, Timothy J. Purwin, Michael A. Davies, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5-9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho-protein expression, we identified cyclin B1, PD-L1, Ets-1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD-L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD-L1 …

Expression Of The Il-11 Gene In Metastatic Cells Is Supported By Runx2-Smad And Runx2-Cjun Complexes Induced By Tgfβ1., Xuhui Zhang, Hai Wu, Jason R. Dobson, Gillian Browne, Deli Hong, Jacqueline Akech, Lucia R. Languino, Gary S. Stein, Jane B. Lian

Department of Cancer Biology Faculty Papers

In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes …

Erbb3-Erbb2 Complexes As A Therapeutic Target In A Subset Of Wild-Type Braf/Nras Cutaneous Melanomas., Claudia Capparelli, Sheera Rosenbaum, Lisa D. Berman-Booty, Amel Salhi, Nadège Gaborit, Tingting Zhan, Inna Chervoneva, Jason Roszik, Scott E. Woodman, Michael A. Davies, Yulius Y. Setiady, Iman Osman, Yosef Yarden, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 …

Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen

Department of Cancer Biology Faculty Papers

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic …

Nf-Κb Regulation Of C-Flip Promotes Tnfα-Mediated Raf Inhibitor Resistance In Melanoma., Yongping Shao, Kaitlyn Le, Hanyin Cheng, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Targeted inhibitors elicit heterogeneous clinical responses in genetically stratified groups of patients. Although most studies focus on tumor intrinsic properties, factors in the tumor microenvironment were recently found to modulate the response to inhibitors. Here, we show that in cutaneous BRAF V600E melanoma, the cytokine tumor necrosis factor-α (TNFα) blocks RAF inhibitor-induced apoptosis via activation of NF-κB. Several NF-κB-dependent factors are upregulated following TNFα and RAF inhibitor treatment. Of these factors, we show that death receptor inhibitor cellular caspase 8 (FLICE)-like inhibitory protein (c-FLIP) is required for TNFα-induced protection against RAF inhibitor. Overexpression of c-FLIP_S or c-FLIP_L isoform decreased RAF …

Paracrine Effect Of Nrg1 And Hgf Drives Resistance To Mek Inhibitors In Metastatic Uveal Melanoma., Hanyin Cheng, Mizue Terai, Ken Kageyama, Shinji Ozaki, Peter Mccue, Takami Sato, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and …

Deregulation Of Mir-34b/Sox2 Predicts Prostate Cancer Progression., Irene Forno, Stefano Ferrero, Maria Veronica Russo, Giacomo Gazzano, Sara Giangiobbe, Emanuele Montanari, Alberto Del Nero, Bernardo Rocco, Giancarlo Albo, Lucia R Languino, Dario C Altieri, Valentina Vaira, Silvano Bosari

Department of Cancer Biology Faculty Papers

Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was …

Chromatin To Clinic: The Molecular Rationale For Parp1 Inhibitor Function., Felix Y. Feng, Johann S. De Bono, Mark A. Rubin, Karen E Knudsen

Department of Cancer Biology Faculty Papers

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have potential clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed.

Dicer1 Regulated Let-7 Expression Levels In P53-Induced Cancer Repression Requires Cyclin D1., Xin Sun, Shou-Ching Tang, Chongwen Xu, Chenguang Wang, Sida Qin, Ning Du, Jian Liu, Yiwen Zhang, Xiang Li, Gang Luo, Jie Zhou, Fei Xu, Hong Ren

Department of Cancer Biology Faculty Papers

Let-7 miRNAs act as tumour suppressors by directly binding to the 3'UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback …

The Endogenous Cell-Fate Factor Dachshund Restrains Prostate Epithelial Cell Migration Via Repression Of Cytokine Secretion Via A Cxcl Signaling Module., Ke Chen, Kongming Wu, Xuanmao Jiao, Liping Wang, Xiaoming Ju, Min Wang, Gabriele Disante, Shaohua Xu, Qiong Wang, Kevin Li, Xin Sun, Chongwen Xu, Zhiping Li, Mathew C. Casimiro, Adam Ertel, Sankar Addya, Peter Mccue, Michael P. Lisanti, Chenguang Wang, Richard J. Davis, Graeme Mardon, Richard Pestell

Department of Cancer Biology Faculty Papers

Prostate cancer is the second leading form of cancer-related death in men. In a subset of prostate cancer patients, increased chemokine signaling IL8 and IL6 correlates with castrate-resistant prostate cancer (CRPC). IL8 and IL6 are produced by prostate epithelial cells and promote prostate cancer cell invasion; however, the mechanisms restraining prostate epithelial cell cytokine secretion are poorly understood. Herein, the cell-fate determinant factor DACH1 inhibited CRPC tumor growth in mice. Using Dach1(fl/fl)/Probasin-Cre bitransgenic mice, we show IL8 and IL6 secretion was altered by approximately 1,000-fold by endogenous Dach1. Endogenous Dach1 is shown to serve as a key endogenous restraint to …

Consequence Of The Tumor-Associated Conversion To Cyclin D1b., Michael A Augello, Lisa D Berman-Booty, Richard Carr, Akihiro Yoshida, Jeffry L Dean, M J Schiewer, Felix Y Feng, Scott A Tomlins, Erhe Gao, Walter J Koch, Jeffrey L Benovic, John Alan Diehl, Karen E Knudsen

Department of Cancer Biology Faculty Papers

Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote …

Kinase-Independent Role Of Cyclin D1 In Chromosomal Instability And Mammary Tumorigenesis., Mathew C Casimiro, Gabriele Disante, Marco Crosariol, Emanuele Loro, William Dampier, Adam Ertel, Zuoren Yu, Elizabeth A Saria, Alexandros Papanikolaou, Z Li, Chenguang Wang, Sankar Addya, Michael P. Lisanti, Paolo Fortina, Robert D Cardiff, Aydin Tozeren, Erik S Knudsen, Andrew Arnold, Richard Pestell

Department of Cancer Biology Faculty Papers

Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1-/- mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led …

Antibiotics For Cancer Therapy., Richard Pestell, Albert A Rizvanov

Department of Cancer Biology Faculty Papers

No abstract provided.

Novel Actions Of Next-Generation Taxanes Benefit Advanced Stages Of Prostate Cancer., Renée De Leeuw, Lisa D. Berman-Booty, Matthew J. Schiewer, Stephen J Ciment, Robert Den, Adam P. Dicker, William Kelly, Edouard J. Trabulsi, Costas D. Lallas, Leonard G. Gomella, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

PURPOSE: To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond.

EXPERIMENTAL DESIGN: Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro …