Extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor, regulate growth and survival of prostate cancer cells.
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.
Dubi
Noga
N
Department of Morphology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, PO Box 653, Beer Sheva 84105, Israel.
Gheber
Larisa
L
Fishman
Daniel
D
Sekler
Israel
I
Hershfinkel
Michal
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004789:Enzyme Activation; D016257:Fura-2 / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D017967:Zinc Compounds / Q000494:pharmacology*
D011956:Receptors, Cell Surface; D017967:Zinc Compounds; C049925:fura-2-am; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium; D016257:Fura-2