Centrosome-Based Mechanisms, Prognostics and Therapeutics in Prostate Cancer; Final rept. 1 Dec 2003-30 Nov 2007

摘要

Centrosomes are involved in mitotic spindle function and are abnormal in prostate tumors. This proposal investigated the role of centrosomes, centrosome proteins and other mitotic structures and processes in prostate cancer. Our results show that the centrosome protein pericentrin is present at the midbody, a structure involved in the final stage of cell division called cytokinesis, where it anchors PKA, PKB/Akt and PKC. Disruption of midbody anchoring (or depletion) of any of these kinases results in cytokinesis failure and aneuploidy, a hallmark of prostate carcinoma. A new asymmetric pathway involved in the completion of cytokinesis was identified and was characterized by asymmetric membrane trafficking, asymmetric positioning of the older centrosome and asymmetric inheritance of the midbody into one of the two daughter cells. Midbodies accumulated in subpopulations of cells in human prostate tumors and prostate cancer cell lines (PC3) but not in nontumor cells. Cancer cells that had midbodies were more aggressive in tumor assays. Midbody- containing cells were found in cells of stem cell niches and in cultured stem cells. We hypothesize that midbodies will serve as markers for prostate cancer stem cells and possibly contribute to therapy-resistant prostate cancers.