TY - JOUR
T1 - Extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor, regulate growth and survival of prostate cancer cells
AU - Dubi, Noga
AU - Gheber, Larisa
AU - Fishman, Daniel
AU - Sekler, Israel
AU - Hershfinkel, Michal
N1 - Funding Information:
Israeli Science Foundation (585/05); Binational Science Foundation (2003201) and German Israeli Foundation, grant number 912-90.11/ 2006 to M.H.
PY - 2008/9/22
Y1 - 2008/9/22
N2 - 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 Gαq 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.
AB - 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 Gαq 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.
UR - http://www.scopus.com/inward/record.url?scp=51849108493&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgn027
DO - 10.1093/carcin/bgn027
M3 - Article
AN - SCOPUS:51849108493
SN - 0143-3334
VL - 29
SP - 1692
EP - 1700
JO - Carcinogenesis
JF - Carcinogenesis
IS - 9
ER -