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Extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor, regulate growth and survival of prostate cancer cells

2008; Oxford University Press; Volume: 29; Issue: 9 Linguagem: Inglês

10.1093/carcin/bgn027

1460-2180

Noga Dubi, Larisa Gheber, Daniel Fishman, Israel Sekler, Michal Hershfinkel,

Heavy Metal Exposure and Toxicity

Prostate Zn 2+ concentrations are among the highest in the body, and a marked decrease in the level of this ion is observed in prostate cancer. Extracellular Zn 2+ is known to regulate cell survival and proliferation in numerous tissues. In spite of this, a signaling role for extracellular Zn 2+ in prostate cancer has not been established. In the present study, we demonstrate that prostate metastatic cells are impermeable to Zn 2+ , but extracellular Zn 2+ triggers a metabotropic Ca 2+ rise that is also apparent in the presence of citrate. Employing fluorescent imaging, we measured this activity in androgen-insensitive metastatic human cell lines, PC-3 and DU-145, and in mouse prostate tumor TRAMP-1 cells but not in androgen-sensitive LNCaP cells. The Ca 2+ response was inhibited by Gαq and phospholipase C (PLC) inhibitors as well as by intracellular Ca 2+ store depletion, indicating that it is mediated by a Gq-coupled receptor that activates the inositol phosphate (IP 3 ) pathway consistent with the previously identified zinc-sensing receptor (ZnR). Zn 2+ -dependent extracellular signal-regulated kinase and AKT activation, as well as enhanced Zn 2+ -dependent cell growth and survival, were observed in PC-3 cells that exhibit ZnR activity, but not in a ZnR activity-deficient PC-3 subline. Interestingly, application of Zn 2+ -citrate (Zn 2+ Cit), at physiological concentrations, was followed by a profound functional desensitization of extracellular Zn 2+ -dependent signaling and attenuation of Zn 2+ -dependent cell growth. Our results indicate that extracellular Zn 2+ and Zn 2+ Cit, by triggering or desensitizing ZnR activity, distinctly regulate prostate cancer cell growth. Thus, therapeutic strategies based either on Zn 2+ chelation or administration of Zn 2+ Cit may be effective in attenuating prostate tumor growth.