The Involvement of Bax in Zinc-Induced Mitochondrial Apoptogenesis in Malignant Prostate Cells

Abstract

BackgroundThe development and progression of prostate cancer requires the transformation of normal zinc-accumulating epithelial cells to malignant cells that have lost the ability to accumulate zinc. This metabolic transformation is essential so that the tumor suppressive effects of zinc can be eliminated and the malignant process can proceed. One of the major effects of zinc is its prevention of prostate cell growth by its induction of apoptosis. The accumulation of cellular zinc has a direct effect on the mitochondria that results in the release of cytochrome c, which initiates the caspase cascade that leads to apoptosis. This effect is associated with the mitochondrial pore-forming process, but the mechanism by which zinc induces the release of cytochrome c and induces mitochondrial apoptogenesis has not been resolved. The present report provides for the first time information that implicates Bax in the zinc induction of mitochondrial apoptogenesis.ResultsThe effects of zinc treatment on the Bax levels of PC-3 cells and on the mitochondria were determined. The exposure of isolated mitochondria to zinc results in an increase in membrane bound Bax, which is due to the mitochondrial insertion of endogenous resident Bax. The mitochondrial Bax/Bcl-2 ratio is increased by zinc treatment. Zinc treatment of PC-3 cells also increases the mitochondrial level of Bax. In addition, zinc treatment increases the cellular level of Bax and the cellular Bax/Bcl2 ratio. Down regulation of Bax in PC-3 cells eliminates the zinc induction of apoptosis. The increase in cellular Bax level appears to involve zinc induction of Bax gene expression.ConclusionThis report extends and confirms that physiological levels of zinc induce apoptosis in prostate cells. The study provides evidence that zinc is directly involved in facilitating a Bax-associated pore formation process that initiates mitochondrial apoptogenesis. This is enhanced by an additional effect of zinc on increasing the cellular level of Bax. To avoid the anti-tumor apoptogenic effects of zinc, the malignant cells in prostate cancer posses genetic/metabolic adaptations that prevent the cellular accumulation of zinc.

The status of zinc in the development of hepatocellular cancer

“…This is further supported by observations that the cytotoxic effects of zinc accumulation in malignant cells are not manifested in the normal cells. [18][19][20] Exposure of malignant cells to physiological concentrations of zinc results in the inhibition of proliferation and induction of apoptosis, 21,22 and also inhibits the important malignancy capabilities such as migration and invasion. Collectively, these actions of zinc on malignant cells constitute "tumor-suppressor" effects of zinc.…”

Zinc as an anti-tumor agent in prostate cancer and in other cancers

“…Therefore, cell proliferation is an essential activity for the progression of malignancy. A consequence of the cellular accumulation of zinc is an inhibitory effect on proliferation of these prostate cells that results from its induction of apoptosis [30][31][32]. This effect results from a direct action of zinc on the mitochondria that causes the release of cytochrome c followed by caspase activation and cascading apoptotic events.…”

Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma

“…[2][3][4] These include: altered bioenergetic/metabolic effects; 2 growth-inhibitory/apoptogenic effects; [17][18][19][20][21][22][23] and cell motility/invasive inhibitory effects. [24][25][26] The depletion of zinc is an essential event to protect the malignant cells from the tumor suppressor effects of zinc.…”