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

Abstract

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 Galphaq 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.

• Authors: Noga Dubi, Larisa Gheber, Daniel Fishman, Israel Sekler, Michal Hershfinkel
• Journal: Carcinogenesis (Carcinogenesis) Vol. 29 Issue 9 Pg. 1692-700 (Sep 2008) ISSN: 1460-2180 [Electronic] England
• PMID: 18310092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Cell Surface
• Zinc Compounds
• fura-2-am
• Phosphatidylinositol 3-Kinases
• Mitogen-Activated Protein Kinases
• Calcium
• Fura-2

Topics

• Animals
• Calcium (metabolism)
• Calcium Signaling
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Enzyme Activation
• Fura-2 (analogs & derivatives, metabolism)
• Humans
• Immunoblotting
• Male
• Mice
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Prostatic Neoplasms (metabolism, pathology)
• Receptors, Cell Surface (metabolism)
• Signal Transduction
• Tumor Cells, Cultured (drug effects)
• Zinc Compounds (pharmacology)