OF PROJECT Role of Rho GDP dissociation inhibitors in androgen signaling in prostate cancer KEYWORDS (MeSH terms only; minimum three) Prostate cancer, androgen receptor, RhoGDI, castration-resistance, proliferation BRIEF STATEMENT OF RESEARCH OBJECTIVES (Do not use continuation sheets) Treatment for disseminated prostate cancer (CaP) is the withdrawal of androgens. However, CaP eventually continues to grow in an androgen-independent or castration-resistant state. Great effort has focused on understanding the mechanisms involved in the development and progression of castration-resistant prostate cancer (CRPC). Androgen receptor (AR) appears to play a central role in the development and progression of CRPC. We have identified a novel signaling molecule namely RhoGDI1, using 2-D gel analysis of protein profile combined with protein sequencing, that is downregulated in prostate cancer and its downregulation plays critical role during prostate cancer progression to CRPC. The levels of RhoGDI1 expression were decreased in prostate cancer tissues compared to benign prostate tissues. Overexpression of RhoGDI1 inhibited the growth of castration-resistant prostate cancer cells and caused a reversal to an androgen-sensitive stage, while downregulation of RhoGDI1 enhanced androgen-sensitive prostate cancer cell growth in androgen-deprived conditions. Furthermore, RhoGDI1 suppressed AR expression and AR activation via interaction with AR. Based on these data, we hypothesize that loss of RhoGDI1 expression promotes the development and progression of prostate cancer by activating the AR signaling pathway. In this proposal, we will study the function of RhoGDI1 and elucidate the molecular pathways of RhoGDI1 interaction with androgen signaling during prostate cancer progression to castration-resistance.
The specific aims are: I. To examine the effects of RhoGDI1 on androgen responsiveness of prostate cancer cells in vitro We will knockdown RhoGDI1 expression in androgen-responsive LNCaP and LAPC-4 human prostate cancer cell lines, and overexpress RhoGDI1 in androgen-independent C4-2 and LNCaP-IL6+ cells to determine the effects of RhoGDI on cell growth and response to androgens. II. To examine the effects of RhoGDI1 on the development and progression of prostate cancer in vivo We will manipulate the levels of RhoGDI1 in prostate cancer cells and examine the effects of such manipulation on the formation and progression of tumors, as well as on the expression of androgen-inducible genes such as PSA in intact and castrated male athymic mice. III. To determine how RhoGDI1 interacts with AR signaling We will pinpoint the site of AR and RhoGDI1 interaction. We will examine if RhoGDI1 affects AR mRNA transcriptional initiation, protein turnover and nuclear translocation and DNA binding activity of AR. RhoGDI1 recruitment to the promoters of androgen responsive genes will be examined by chromatin immunoprecipitation (ChIP) assays. Potential impact on Veterans health care: Prostate cancer now exceeds lung cancer as the most commonly diagnosed cancer in the United States men, and it is the second leading cause of cancer death in that same population. A very large portion of men with prostate cancer are treated successfully with androgen deprivation therapy. However, virtually all patients will relapse due to acquisition of the growth of castration resistant tumor cells. Unfortunately, there is currently no effective treatment for men with castration resistant prostate cancer. The present proposal directly deals with the mechanisms of this evolution of castration resistant prostate cancer and has identified a critical factor involved in this process. Thus, this project targets castration resistant prostate cancer, a very significant health problem among male veterans. Our important mechanistic and pre-clinical studies will serve as the foundation for development of a mechanism based castration-adjunctive therapy, which may lead to a more effective intervention than castration alone. VA FORM 10-1313-2 Page 2 of VA Form 10-1313 package JUN 1990(R)
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