Resveratrol mobilizes Ca2+ from intracellular stores and induces c-Jun N-terminal kinase activation in tumoral AR42J cells

Resveratrol (3,4′,5-trihydroxy- trans -stilbene), a phytoalexin naturally found in grapes and red wine, is a redox-active compound endowed with significant positive activities. In this study, the effects of resveratrol on intracellular free Ca 2+ concentration ([Ca 2+ ] c ) and on cell viability in tumoral AR42J pancreatic cells are examined. The results show that resveratrol (100 μM and 1 mM) induced changes in [Ca 2+ ] c , that consisted of single or short lasting spikes followed by a slow reduction toward a value close to the resting level. Lower concentrations of resveratrol (1 and 10 μM) did not show detectable effects on [Ca 2+ ] c . Depletion of intracellular Ca 2+ stores by stimulation of cells with 1 nM CCK-8, 20 pM CCK-8 or 1 μM thapsigargin, blocked Ca 2+ responses evoked by resveratrol. Conversely, prior stimulation of cells with resveratrol inhibited Ca 2+ mobilization in response to a secondary application of CCK-8 or thapsigargin. In addition, resveratrol inhibited oscillations in [Ca 2+ ] c evoked by a physiological concentration of CCK-8 (20 pM). On the other hand, incubation of cells in the presence of resveratrol induced a reduction of cell viability. Finally, incubation of AR42J cells in the presence of resveratrol led to activation of c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase responsive to stress stimuli. Activation of JNK was reduced in the absence of extracellular Ca 2+ . In summary, the results show that resveratrol releases Ca 2+ from intracellular stores, most probably from the endoplasmic reticulum, and reduces AR42J cells viability. Reorganization of cell’s survival/death processes in the presence of resveratrol may involve Ca 2+ -mediated JNK activation.