Regulation of caspase activation and apoptosis by cellular zinc fluxes andzinc deprivation: A review

Non-toxic agents that target intracellular signalling pathways in apoptosis may have potential therapeutic use in many diseases. One such agent is the transition metal Zn, a dietary cytoprotectant and anti-oxidant, which stim ulates cell proliferation and suppresses apoptosis. Zn is maintained in dis crete subcellular pools that are critical for the functional and structural integrity of cells. The present review initially describes the current sta te of knowledge on the cellular biology of Zn, especially the critical free or loosely bound (labile) pools of Zn, which are thought to regulate apopt osis. We then review the evidence relating Zn to apoptosis, including studi es from our laboratory showing potent synergy between intracellular Zn defi ciency and the short chain fatty acid butyrate in induction of caspase acti vation and the downstream events of apoptosis. Our studies have also report ed the suppressive effects of micromolar concentrations of Zn on caspase-3 activation in cell-free models. Other key issues that will be discussed inc lude the identification of the putative molecular targets of Zn and the evi dence that systemic changes in labile Zn levels are sufficient to alter sus ceptibility to apoptosis and lead to physiopathological changes in the huma n body. Finally, we propose that labile Zn may serve as a coordinate regula tor of mitosis and apoptosis to regulate tissue growth.