DAVID DANIELPOUR, PhDProfessor
General Medical Sciences (Oncology)
Function and Regulation of a TGF-Β in the Prostate
My laboratory focuses on the role of transforming growth factor-beta (TGF-Β) as a tumor suppressor and regulator of growth, apoptosis and androgenic responses in the prostate. An important role for TGF-Β in androgenic control of the prostate has been previously implicated by a number of in vivo studies which showed androgens negatively regulate expression of TGF-Βs, TGF-Β receptors (TΒRI and TΒRII) and activation of rSmads (Smads 2 and 3) in the prostate. The normal cellular responses to TGF-Βs are lost or altered during prostatic carcinogenesis, concomitant with loss of TGF-Β receptor levels and loss of androgen dependence, implicating a role for TGF-Β signaling in regulation of androgen dependence and tumor suppression. To test this latter role, we disrupted the function of TGF-Β receptors in non-tumorigenic rat prostate epithelial cell lines, NRP-152 and DP-153, by over-expressing a truncated TΒRII that functions as a dominant-negative receptor (DNR). Overexpression of this DNR by retroviral transduction resulted in the malignant transformation of NRP-152 and DP-153 as assessed by s.c. tumor in athymic mice. These data fully support TGF-Β's role as a tumor suppression of the prostate.
Using primary prostate epithelial cell lines developed in my laboratory, we were first to report that TGF-Β can directly induce apoptosis of isolated prostatic cells in culture. Since then an important focus of our work has been to understand how TGF-Β induces apoptosis and how this mechanism is altered in prostate cancer. Using our cell culture system, we have demonstrated that TGF-Β induces the release of cytochrome c and the subsequent activation of caspases -9 and -3. We showed that TGF-Β may promote apoptosis by down-regulating the expression of the anti-apoptotic proteins Bcl-xl and survivin through distinct mechanisms. Survivin is an inhibitor of apoptosis protein (IAP) whose overexpression is tightly correlated with the aggressiveness of prostate cancer and is believed to play a role in chemo- and hormone-resistance in advanced prostate cancer. We have shown that an intact TGF-Β signaling pathway in pre-neoplastic prostate epithelial cells suppresses the activity of the survivin gene promoter through activating the retinoblastoma protein (Rb) and/or other pocket proteins (by a Smad-dependent mechanism), which then interact with CHR and CDE elements in the proximal region of the survivin promoter.
A second focus of this laboratory is to investigate the mechanisms governing loss of tumor suppression by TGF-Β during prostate cancer progression. Along these lines we have provided evidence that activation of the androgen receptor (AR) and the IGF-I/ PI3K/Akt/mTOR pathway, inactivation of the retinoblastoma protein (Rb) and induced expression of the LIM domain protein Hic-5 in prostate cancer may disrupt the tumor suppressive function of TGF-Β. Some of these pathways may also be important contributors to switching the function of TGF-Β from a tumor suppressor to that of an oncogene, a phenomenon associated with late-stage cancers. Understanding these mechanisms is likely to aid in the development of therapeutic strategies for the intervention of prostate cancer.
We recently made a novel discovery that Smad2 functions as a critical tumor suppressor in prostate epithelial cells. We showed that silencing the expression of Smad2 alone (by lentiviral-mediated shRNA) can promote the malignant transformation of NRP-152 cells. This has opened investigation of the role of Smad2 as a suppressor of the prostate, and we are now exploring potential changes in the posttranslational modification of Smad2 that may occur during prostate carcinogenesis.
Wahdan-Alaswad R, Bane KL, Song K, Krebs TL, Sholar DT, Garcia JA and Danielpour D. Inhibition of mTORC1 Kinase Activates Smads 1 and 5 but not Smad8 in Human Prostate Cancer Cells, Mediating Cytostatic Response to Rapamycin, Molecular Cancer Research, 10:821-33, 2012.
Jinwei Du 1, Yu Chen, Qiang Li 1, Cindy Cheng, Zhengqi Wang, David Danielpour, Sally L. Dunwoodie, Kevin D. Bunting and Yu-Chung Yang. HIF-1α Deletion Partially Rescues Defects of Hematopoietic Stem Cell Quiescence Caused by Cited2 Deficiency, BLOOD,119:2789-98, 2012.
Shola DT, Wang H., Wahdan-Alaswad R and Danielpour D. Hic-5 Controls BMP4 Responses in Prostate Cancer Cells through Interacting with Smads 1, 5 and 8 Oncogene 31:2480-90, 2012.
Yu S, Zhang Y, Yuen MT, Zou C, Danielpour D, Chan FL. 17-beta-estradiol induces neoplastic transformation in prostatic epithelial cells. Cancer Lett 304:8-20, 2011.
Cipriano R, Kan CE, Graham J, Danielpour D, Stampfer M, Jackson MW. TGF-β signaling engages an ATM-CHK2-p53-independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells. Proc Natl Acad Sci U S A 108:8668-8673, 2011. PMCID: PMC3102347
Araki S, Eitel JA, Batuello CN, Bijangi-Vishehsaraei K, Xie XJ, Danielpour D, Pollok KE, Boothman DA, Mayo LD. TGF-beta1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer. J Clin Invest 120:290-302, 2010. PMCID: PMC2798681
Pasupuleti N, Matsuyama S, Voss O, Doseff AI, Song K, Danielpour D, Nagaraj RH. The anti-apoptotic function of human aA-crystallin is directly related to its chaperone activity. Cell Death Dis 1:e31, 2010.
Song K, Wang H, Krebs TL, Wang B, Kelley TJ, Danielpour D. DHT selectively reverses Smad3-mediated/TGF-beta-induced responses through transcriptional down-regulation of Smad3 in prostate epithelial cells. Mol Endocrinol 24:2019-2029, 2010. PMCID: PMC2954637
Wahdan-Alaswad RS, Song K, Krebs TL, Shola DT, Gomez JA, Matsuyama S, Danielpour D. Insulin-like growth factor I suppresses bone morphogenetic protein signaling in prostate cancer cells by activating mTOR signaling. Cancer Res 70:9106-9117, 2010.
Morley S, Thakur V, Danielpour D, Parker R, Arai H, Atkinson J, Barnholtz-Sloan J, Klein E, Manor D. Tocopherol transfer protein sensitizes prostate cancer cells to vitamin E. J Biol Chem 285:35578-35589, 2010. PMCID: PMC2975182
Yang J, Wahdan-Alaswad R, Danielpour D. Critical role of Smad2 in tumor suppression and transforming growth factor-beta-induced apoptosis of prostate epithelial cells. Cancer Res 69:2185-2190, 2009.
Gama V, Gomez JA, Mayo LD, Jackson MW, Danielpour D, Song K, Haas AL, Laughlin MJ, Matsuyama S. Hdm2 is a ubiquitin ligase of Ku70-Akt promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization. Cell Death Differ 16:758-769, 2009. PMCID: PMC2669846
Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 16:9-20, 2009.
Gomez JA, Sun W, Gama V, Hajkova D, Yoshida T, Wu Z, Miyagi M, Pink JJ, Jackson MW, Danielpour D, Matsuyama S. The C-terminus of interferon gamma receptor beta chain (IFNgammaR2) has antiapoptotic activity as a Bax inhibitor. Cancer Biol Ther 8:1771-1786, 2009.
Nastiuk KL, Yoo K, Lo K, Su K, Yeung P, Kutaka J, Danielpour D, Krolewski JJ. FLICE-like inhibitory protein blocks transforming growth factor beta 1-induced caspase activation and apoptosis in prostate epithelial cells. Mol Cancer Res 6:231-242, 2008.
Li N, Zheng L, Lin P, Danielpour D, Pan Z, Ma J. Overexpression of Bax induces down-regulation of store-operated calcium entry in prostate cancer cells. J Cell Physiol 216:172-179, 2008.
Garcia JA, Danielpour D. Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies. Mol Cancer Ther 7:1347-1354, 2008. PMCID: PMC2587303
Nam JS, Terabe M, Mamura M, Kang MJ, Chae H, Stuelten C, Kohn E, Tang B, Sabzevari H, Anver MR, Lawrence S, Danielpour D, Lonning S, Berzofsky JA, Wakefield LM. An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Res 68:3835-3843, 2008. PMCID: PMC2587151
Yang J, Song K, Krebs TL, Jackson MW, Danielpour D. Rb/E2F4 and Smad2/3 link survivin to TGF-beta-induced apoptosis and tumor progression. Oncogene 27:5326-5338, 2008.
Wang H, Song K, Krebs TL, Yang J, Danielpour D. Smad7 is inactivated through a direct physical interaction with the LIM protein Hic-5/ARA55. Oncogene 27:6791-6805, 2008.
Song K, Wang H, Krebs TL, Kim SJ, Danielpour D. Androgenic control of transforming growth factor-beta signaling in prostate epithelial cells through transcriptional suppression of transforming growth factor-beta receptor II. Cancer Res 68:8173-8182, 2008. PMCID: PMC2596934