Mechanism of Prostate Cancer Inhibition by LHRH Analogs

Tuskegee University, Tuskegee Institute AL

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Abstract

DESCRIPTION (provided by applicant): At the time of diagnosis, more than half of prostate tumors have invaded and metastasized. Even early detection of prostate cancer does not always result in cures as the tumors quickly become hormone-independent. Thus, it is imperative that we understand the biology of tumor growth regulation to define new therapeutic targets. Luteinizing hormone releasing hormone (LHRH) and its analogs directly inhibit growth of human, androgen-independent prostate cell lines, including DU- 145. The mechanism by which these analogs exert their antiproliferative effects is unknown. We propose that LHRH agonists limit the pro-growth signaling through the EGF receptor. We have previously shown that: 1) DU-l45 cells growth and invasion are mediated through the epidermal growth factor receptor (EGFR), and 2) EGFR-signaled cell responses are subject to PKC-mediated negative transmodulation by direct phosphorylation of the EGFR. Although the data on LHRH signaling in prostate cells is still uncertain, LHRH agonists stimulate phospholipase-C (PLC) activity in mammary tumors in a similar manner as LHRH does in the pituitary gland. Our model has PLC activity generating diacylglycerol (DAG) and mobilizing intracellular Ca2+ to activate protein kinase C (PKC). These findings lead 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 propose to elucidate LHRH signaling mechanisms for cell proliferation and invasiveness in DU-145 cells under in vitro and in vivo conditions utilizing a potent LHRH analog. Our specific aims for this study are to: 1) Determine whether LHRH analogs prevent prostate tumor growth and/or invasion and progression in vitro and in vivo. 2) Determine whether LHRH analogs can influence cell adhesion. 3) Determine whether LHRH analogs achieve their effects via FKC-mediated transmodulation. The successful completion of this project will elucidate the intra-cellular mechanism by which LHRH analogs exert their antiproliferative effect. This will identify intracellular pathways whose disruption hold promise for restricting prostate cancer progression.