Carcinogenesis Advance Access originally published online on February 28, 2008
Carcinogenesis 2008 29(9):1692-1700; doi:10.1093/carcin/bgn027
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Extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor, regulate growth and survival of prostate cancer cells
Department of Morphology
1 Department of Clinical Biochemistry
2 Department of Chemistry, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, PO Box 653, Beer Sheva 84105, Israel
3 Department of Physiology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, PO Box 653, Beer Sheva 84105, Israel
* To whom correspondence should be addressed. Tel: +972 8 6477318; Fax: +972 8 6477627; Email: hmichal{at}bgu.ac.il
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 G
q 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.
Abbreviations: ATP, adenosine triphosphate; CaEDTA, calcium ethylenediamine tetra-acetic acid; ERK, extracellular signal-regulated kinase; GPCR, G-protein-coupled receptor; IP3, inositol phosphate; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide-3 kinase; PKC, protein kinase C; TG, thapsigargin; ZnR, zinc-sensing receptor; Zn2+Cit, Zn2+-citrate
Received October 10, 2007; revised December 21, 2007; accepted January 19, 2008.
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