David Danielpour, PhD

Case Comprehensive Cancer Center
Associate Professor
Department of Urology
School of Medicine
Associate Professor
Department of Pharmacology
School of Medicine
Molecular Oncology Program
Case Comprehensive Cancer Center

Research Information

Research Projects

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.