Barnholtz-Sloan, Jill

Danielpour, David

DiFeo, Analisa

Guda, Kishore

Jacobberger, James

Leahy, Patrick

Pink, John

Schiemann, William

Sun, Shuying

Veigl, Martina

Member Directory

DAVID DANIELPOUR, PhD Associate Professor General Medical Sciences (Oncology) Phone: 216.368.5670 Fax: 216.368.8919 email: dxd49@case.edu

Research Interests

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.

Recent Publications

Araki S, Bijangi K, Danielpour D, Pollok KE, Boothman DA and Mayo LD. TGF-beta1-induced Expression of Human Mdm2 Correlates with Late-Stage Metastatic Breast Cancer, Journal of Clinical Investigation, 120:290-302, 2010.

Pasupuleti NR, Matsuyama S, Voss O, Doseff AI, Song K, Danielpour D, and Nagaraj RH. Anti-apoptotic function of Human αA-Crystallin is Directly Related to its Chaperone Function, Cell Death and Disease (2010) 1, e31; doi:10.1038/cddis

Song K, Wang H, Krebs TL. Wang BH, Kelley TJ and Danielpour D. Dihydrotestosterone downregulates expression of Smad3 through a transcriptional mechanism to protect prostate epithelial cells against TGF-β-induced apoptosis. Molecular Endocrinology, 24:2019-2029, 2010.

Wahdan-Alaswad R, Song K, Krebs TL, Sholar DT, Gomez JA, Matsuyama S, and Danielpour D. IGF-I Suppresses BMP Signaling in Prostate Cancer Cells by Activating mTOR Signaling. Cancer Research 70:9106-9117, 2010.

Morley S, Thakur V, Danielpour D, Parker R, Arai H, Atkinson J, Barnholtz-Sloan J, Klein E, Manor D. The tocopherol transfer protein sensitizes prostate cancer cells to vitamin E. J. Biol. Chem. 285(46):35578-89, 2010.

Yang, J, Wahdan-Alaswad, R., Danielpour, D. Critical role of Smad2 in Tumor Suppression and TGF-Β-induced apoptosis of prostate epithelial cells. Cancer Res, 69: 2185-2190, 2009.

Gama, V, Gomez, JA, Mayo, LD, Danielpour, D, Song, K, Jackson, MW, Haas, AL, Matsuyama, S. Hdm2 is a Ubiquitin Ligase of Ku70-Akt that promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization, Cell Death and Differentiation, 16:758-769, 2009.

Miao, H, Li, DQi Mukherjee, A, Johnson, E, Cutter, J, Basilion, J , Sedor, J, Wu, J, Danielpour, D,, Sloan, AE, Cohen, ML, Wang BC. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration through 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, 8:55-70, 2009.

Nastuik KL, Yoo K, Lo K, Su, K, Yeung, P, Katuka, J, Danielpour, D, Krolewski, JJ. FLICE-like inhibitory protein blocks TGF-Β1 induced caspase activation and apoptosis in prostate epithelial cells, Mol. Cancer Res. 6: 231-342, 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., 216:172-9, 2008.

Garcia JA and Danielpour D. Mammalian target of rapamycin inhibition as a therapeutic strategy for urologic malignancies. Mol Cancer Thera, 6:1347-54, 2008.

Nam, J-S., Terabe, M., Mamura, M., Kang, M-J., Chae,H., Stuelten, C., Kohn, E., Tang, B., Sabzevari,H., Anver, M.R., Lawrence, A., Danielpour,D., Lonning, S., Berzofsky, J., Wakefield, L.M., An anti-TGF-Β antibody suppresses metastasis via cooperative effects on multiple cellular compartments. Cancer Res. 68:3835-43, 2008.

Yang J, Song K, Krebs TL, Jackson MW, Danielpour D. Rb/E2F4 and Smad2/3 link survivin to TGF-Β induced apoptosis and tumor progression. Oncogene, Sep 11;27(40):5326-38, 2008. 2008.

Wang H, Song K, Yang J, Krebs TL, Danielpour D. The LIM protein Hic-5/ARA55 controls TGF-Β signaling through a direct physical interaction with Smad7. Oncogene, Nov 20;27(54):6791-805, 2008.

Song K, Wang H, Krebs TL, Danielpour D. Androgenic Control of TGF-Β Signaling in Prostate Epithelial Cells through Transcriptional Suppression of TGF-Β Receptor II. Cancer Res.;68: 8173-82, 2008.