Dubi Noga, Gheber Larisa, Fishman Daniel, Sekler Israel, Hershfinkel Michal
Department of Morphology, Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University, PO Box 653, Beer Sheva 84105, Israel.
Carcinogenesis. 2008 Sep;29(9):1692-700. doi: 10.1093/carcin/bgn027. Epub 2008 Feb 28.
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.
前列腺中的锌离子（Zn(2+)）浓度是人体中最高的之一，在前列腺癌中可观察到这种离子水平显著下降。已知细胞外锌离子可调节许多组织中的细胞存活和增殖。尽管如此，细胞外锌离子在前列腺癌中的信号传导作用尚未确立。在本研究中，我们证明前列腺转移细胞对锌离子不可渗透，但细胞外锌离子会引发代谢型钙离子升高，在存在柠檬酸盐的情况下这种升高也很明显。利用荧光成像技术，我们在雄激素不敏感的转移性人细胞系PC-3和DU-145以及小鼠前列腺肿瘤TRAMP-1细胞中测量了这种活性，但在雄激素敏感的LNCaP细胞中未检测到。钙离子反应受到Gαq和磷脂酶C（PLC）抑制剂以及细胞内钙离子储存耗竭的抑制，这表明它是由与先前鉴定的锌离子感应受体（ZnR）一致的Gq偶联受体介导的，该受体激活肌醇磷酸（IP(3)）途径。在具有ZnR活性但在ZnR活性缺陷的PC-3亚系中未观察到的PC-3细胞中，观察到了锌离子依赖性细胞外信号调节激酶和AKT的激活，以及增强的锌离子依赖性细胞生长和存活。有趣的是，在生理浓度下应用柠檬酸锌（Zn(2+)Cit）后，细胞外锌离子依赖性信号传导会发生显著的功能脱敏，锌离子依赖性细胞生长也会减弱。我们的结果表明，细胞外锌离子和Zn(2+)Cit通过触发或使ZnR活性脱敏，明显调节前列腺癌细胞的生长。因此，基于锌离子螯合或Zn(2+)Cit给药的治疗策略可能对减轻前列腺肿瘤生长有效。
