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Prostate Zn2+concentrations are among the highest in the body, and a marked decrease in the level of this ion is observed in prostate cancer. Extracellular Zn2+is known to regulate cell survival and proliferation in numerous tissues. In spite of this, a signaling role for extracellular Zn2+in prostate cancer has not been established. In the present study, we demonstrate that prostate metastatic cells are impermeable to Zn2+, but extracellular Zn2+triggers a metabotropic Ca2+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 Ca2+response was inhibited by Gαq and phospholipase C (PLC) inhibitors as well as by intracellular Ca2+store depletion, indicating that it is mediated by a Gq-coupled receptor that activates the inositol phosphate (IP3) pathway consistent with the previously identified zinc-sensing receptor (ZnR). Zn2+-dependent extracellular signal-regulated kinase and AKT activation, as well as enhanced Zn2+-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 Zn2+-citrate (Zn2+Cit), at physiological concentrations, was followed by a profound functional desensitization of extracellular Zn2+-dependent signaling and attenuation of Zn2+-dependent cell growth. Our results indicate that extracellular Zn2+and Zn2+Cit, by triggering or desensitizing ZnR activity, distinctly regulate prostate cancer cell growth. Thus, therapeutic strategies based either on Zn2+chelation or administration of Zn2+Cit may be effective in attenuating prostate tumor growth.

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