Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc 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 stimulates cell proliferation and suppresses apoptosis. Zn is maintained in discrete subcellular pools that are critical for the functional and structural integrity of cells. The present review initially describes the current state of knowledge on the cellular biology of Zn, especially the critical free or loosely bound (labile) pools of Zn, which are thought to regulate apoptosis. We then review the evidence relating Zn to apoptosis, including studies from our laboratory showing potent synergy between intracellular Zn deficiency and the short chain fatty acid butyrate in induction of caspase activation and the downstream events of apoptosis. Our studies have also reported the suppressive effects of micromolar concentrations of Zn on caspase-3 activation in cell-free models. Other key issues that will be discussed include the identification of the putative molecular targets of Zn and the evidence that systemic changes in labile Zn levels are sufficient to alter susceptibility to apoptosis and lead to physiopathological changes in the human body. Finally, we propose that labile Zn may serve as a coordinate regulator of mitosis and apoptosis to regulate tissue growth.
Chai
F
F
Department of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
Truong-Tran
A Q
AQ
Ho
L H
LH
Zalewski
P D
PD
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002087:Butyrates / Q000494:pharmacology; D020169:Caspases / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D015032:Zinc / Q000502:physiology*
D002087:Butyrates; D002614:Chelating Agents; D005029:Ethylenediamines; D020169:Caspases; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine