Prostate cancer is the most predominant cancer in men 'in the United States. At time of diagnosis. more than half I of these tumors have already invaded or metastasized. This stage of prostate cancer progression invariable leads to patient death since once the tumor escapes its local confines no curative therapies for this disease exist. Therefore, it is paramount that studies are directed at better understanding the biology of tumor progression and instituting therapies preventing or limiting the prostate tumors transition to more aggressive invasive and metastatic stages. Recently, analogs to luteinizing hormone releasing hormone (LHRH) have been shown to have i antiproliferative actions on the human, androgen-independent prostate cell line, DU-145. Upon binding its receptor, LHRH signaling pathways are mediated by phospholipase C (PLC) activity. PLC in turn generates diacylglycerol (DAG) and mobilizes intracellular calcium. These second messengers activate protein lin7e C (PKQ; PKC phosphorylates numerous enzymes directly responsible for the final biological effects of the hormone. We have previously shown that: 1) DU-145 cells growth and invasion are mediated through the epidermal growth factor receptor (EGFR), and 2) EGFR-signaled ceU responses are subject to PKC-mediated negative transmodulation. These findings have lead us to hypothesize that the antiproliferative effects of LXH C. agonists arc mediated through negative attenuation of the EGFR which is inactivated by phosphorylation b, KC. We propose to elucidate LHRH signafing mechanism for cell proliferation and invasiveness in DU-145 ce& under in vitro conditions utilizing potent LHRH agonists.
Our specific aims for this study are: 1) To ascertain if LHRH analogues are cytotoxic to and capable of inhibiting DU-145 cell invasiveness i . n Wtro. 2) Determine whether LHRH analogues attenuate EGFR signaling via PKC-mediated transmodulation. 3) Determine the ability of LHRH I analogs to alter adhesive condition s of DU-145 sublines. The completion of this research will ultimately provide I answers to distinguish- which tumor cell property is targeted by LERH agonists and the mitracellular mechanism by which this is accomplished. Consequently identifying novel intracellular signaling pathways whose disruption hold promise for restricting prostate cancer progression.
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