Novel Role of Candidate Tumor Suppressor ANX7 Gene in Prostate Cancer; Final rept. 1 Mar 2003-28 Feb 2006

摘要

A detailed analysis of ANX7 levels in hundreds of prostate cancer specimens revealed that expression of this candidate tumor suppressor gene is specifically altered in metastatic and hormone refractory prostate cancers. Overexpression of ANXA7 killed prostate cancer cells by apoptosis. So we hypothesized that the ANX7 gene kills prostate cancer cells by increasing IP3- Receptor expression thereby potentiating the IP3-dependent apoptotic calcium signaling pathway. We found that the ANX7 induced apoptotic pathway involves calcium and cytochrome c release indicating the probable involvement of mitochondria. ANX7 induces morphological changes including cell shrinkage nuclear fragmentation and chromatin condensation. Overexpression of ANX7 or the ANX7J mutant in DU145 cells does not alter basal (Ca2+)i levels. However overexpression of ANX7 reduces the percentage of cells that are capable of responding to the IP3-generating agonist acetylcholine. Furthermore overexpression of either ANX7 or the ANX7J-mutant may be associated with a reduction in the magnitude of the response to acetylcholine. We identified using cDNA microarrays the apoptosis metastatic and cell cycle 'corrected' genes which show equivalent relative expression in PREC normal prostate cells and transfected metastatic DU145 cancer cells with wt-ANX7 or P53.