Mechanisms of resveratrol-induced changes in [Ca²⁺]i and cell viability in PC3 human prostate cancer cells

Resveratrol is a natural compound that affects cellular Ca²⁺ homeostasis and viability in different cells. This study examined the effect of resveratrol on cytosolic free Ca²⁺ concentrations ([Ca ²⁺]i) and viability in PC3 human prostate cancer cells. The Ca ²⁺-sensitive fluorescent dye fura-2 was used to measure [Ca ²⁺]i and WST-1 was used to measure viability. Resveratrol-evoked [Ca²⁺]i rises concentration-dependently. The response was reduced by removing extracellular Ca²⁺. Resveratrol-evoked Ca²⁺ entry was not inhibited by nifedipine, econazole, SKF96365 and the protein kinase C inhibitor GF109203X, but was nearly abolished by the protein kinase C activator phorbol 12-myristate 13 acetate. In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor 2,5-di-tert- butylhydroquinone decreased resveratrol-evoked rise in [Ca²⁺]i. Conversely, treatment with resveratrol inhibited BHQ-evoked rise in [Ca ²⁺]i. Inhibition of phospholipase C with U73122 did not alter resveratrol-evoked rise in [Ca²⁺]i. Previous studies showed that resveratrol between 10 and 100M induced cell death in various cancer cell types including PC3 cells. However, in this study, resveratrol (1-10μM) increased cell viability, which was abolished by chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetra-acetic acid-acetoxymethyl ester (BAPTA/AM). Therefore, it is suggested that in PC3 cells, resveratrol had a dual effect on viability: at low concentrations (1-10M) it induced proliferation, whereas at higher concentrations it caused cell death. Collectively, our data suggest that in PC3 cells, resveratrol-induced rise in [Ca²⁺]i by evoking phospholipase C-independent Ca ²⁺ release from the endoplasmic reticulum and Ca²⁺ entry, via protein kinase C-regulated mechanisms. Resveratrol at 1-10M also caused Ca²⁺-dependent cell proliferation.