Centrosome-Based Mechanisms, Prognostics and Therapeutics in Prostate Cancer

Abstract

Abstract : Centrosomes are tiny structures critical for organizing mitotic spindles and segregating chromosomes during mitosis. We (and another group) were the first to discover that centrosomes were abnormal in nearly all malignant human tumors. Our recent observations show that centrosome defects and genomic instability can be artificially induced by elevating the levels of the centrosome protein pericentrin and that pericentrin was elevated in prostate carcinomas. Based on these observations, we proposed that centrosome dysfunction may be a critical factor in prostate cancer progression that could explain most phenotypic changes that occur during progression of prostate carcinomas. The specific aims of the original proposal were designed to test several features of this model. 1. Are centrosome defects present in early prostate cancer and can they predict aggressive disease? 2. Do pericentrin s oncogenic features result from the interaction with PKA,PKB/Akt and/or PKC? 3. Can prostate tumor cells be arrested in the cell by overexpression of a pericentrin domain that blocks the cell cycle? We anticipate that this work will lead to new prognostic markers and novel cancer-specific therapeutic targets for aggressive prostate cancer, the form that is most critical in terms of diagnosis, treatment and health care expenditure.