Carcinogenesis Advance Access published online on February 28, 2008
Carcinogenesis, 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
1 Department of Morphology, and the Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, POB 653, Beer Sheva, 84105, Israel
2 Clinical Biochemistry, and the Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, POB 653, Beer Sheva, 84105, Israel
3 Chemistry, and the Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, POB 653, Beer Sheva, 84105, Israel
4 Physiology and the Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, POB 653, Beer Sheva, 84105, Israel
Address correspondence to: Michal Hershfinkel, Department of Morphology, Faculty of Health Sciences, Ben-Gurion University, POB 653, Beer Sheva, 84105, Israel, Tel: 972-8-6477318, E-mail: 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 PLC inhibitors as well as by intracellular Ca2+-store depletion, indicating that it is mediated by a Gq-coupled receptor that activates the IP3 pathway consistent with the previously identified zinc sensing receptor (ZnR). Zn2+-dependent ERK 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, 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+-citrate, by triggering or desensitizing ZnR activity, distinctly regulate prostate cancer cell growth. Thus, therapeutic strategies based either on Zn2+ chelation or administration of Zn2+-citrate may be effective in attenuating prostate tumor growth
Received October 10, 2007; revised December 21, 2007; accepted January 19, 2008.
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