The normal prostate gland accumulates the highest level of zinc among all the soft tissue in the body, along with the highest production of citrate. In contrast, prostate cancer is characterized by a dramatic decrease in prostatic zinc levels. However, neither the association of the loss of zinc with pathogenesis in the prostate gland, nor the mechanisms of low levels of zinc related to the progression of prostate cancer have been adequately explored. We recently demonstrated that zinc induces apoptosis in prostate cancer cells. In these cells, the apoptosis induced by zinc involved the accumulation of intracellular zinc, the cytochrome c release from mitochondria and the activation of the caspase cascade. Preliminary studies also revealed that activation and translocation of Bax to mitochondria are involved in the zinc-induced mitochondrial apoptosis pathway; the expression of Bax appears to be up-regulated by zinc; and this apoptotic effect of zinc is cell type specific. However, gaps exist in the understanding of the molecular mechanisms of the zinc-induced apoptosis pathway in prostate cancer cells. Thus, we hypothesize: the restoration of zinc in malignant prostate cells induces cell specific alterations in cellular and mitochondrial function that result in the release of cytochrome c leading to mitochondria mediated apoptosis. Moreover, the zinc induced cytochrome c release results from an effect of zinc on the activation, mitochondrial translocation, and the gene expression of Bax. To test this hypothesis three specific aims are proposed: (1) to define the molecular mechanism of zinc induced activation of Bax in prostate cell mitochondria; (2) to establish the mechanism of the zinc upregulation of Bax gene expression and associated increase of cellular Bax level; and (3) to determine the target pathway or factors which govern the cell specificity in response to the apoptotic effect of zinc. The completion of these aims will contribute to our understanding of the zinc effect on the pathogenesis of prostate cancer development. The elucidation of the molecular basis of the cell specific response to zinc restoration in prostate cancer cells will contribute to the development of new approaches to the treatment of prostate cancer.
| Lin, Shu-Fei; Wei, Hua; Maeder, Dennis et al. (2009) Profiling of zinc-altered gene expression in human prostate normal vs. cancer cells: a time course study. J Nutr Biochem 20:1000-12 |
| Feng, Pei; Li, Tieluo; Guan, Zhixin et al. (2008) The involvement of Bax in zinc-induced mitochondrial apoptogenesis in malignant prostate cells. Mol Cancer 7:25 |
