IDENTIFYING SIGNALING PATHWAYS PROSTATE TUMOR INHIBITION BY LHRH ANALOGS

Tuskegee University, Tuskegee Institute AL

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prostate cancer continues to be the most prevalent cancer in men residing in the United States of America. The effects of this disease on the African American community has been even more devastating, with African American males having the highest incidence and mortality rate of any ethnic group in America. The long-term, overall thrust of this project was to understand the intricate signaling mechanisms involved in the crosstalk between the luteinizing hormone releasing hormone (LHRH) analog, Cetrorelix and the epidermal growth factor receptor (EGFR) in prostate cancer cell proliferation and invasion. We believed gaining insight into these cellular interactions would play a role in the development of therapies directed at preventing or limiting prostate tumor transition to the more aggressive invasive and metastatic stages, as well as offer different benefits than those therapies targeting early carcinogenic steps. Previous reports in the literature supporting a direct route for LHRH analogs to produce antiproliferative actions on the human, androgen-independent prostate cell line, DU-145 coupled with our data showing that: 1) DU-145 in vivo and in vitro cell growth and invasion are mediated through EGFR and 2) EGFR-signaled cell responses are subject to protein kinase C (PKC)-mediated negative transmodulation led us to hypothesize that the antiproliferative effects of LHRH agonists are mediated through negative attenuation of the EGFR which is inactivated by phosphorylation by PKC. We proposed to elucidate LHRH signaling mechanism for cell proliferation and invasiveness in human prostate carcinoma-derived DU-145 cells under in vitro conditions utilizing the potent LHRH analog, Cetrorelix. Our specific aims were to: 1) Determine whether LHRH analogs prevent prostate tumor growth and/or invasion and progression in vitro. 2) Determine whether LHRH analogs can influence cell adhesion. 3) Determine whether LHRH analogs achieve their effects via PKC-mediated transmodulation. 4) Determine the cytotoxicity of synthetic peptides on prostate cancer cell lines.