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.
Department of Physiology, University of Extremadura, Caceres, Spain.
Lourdes
L
Garcia-Sanchez
Patricia
P
Santofimia-Castaño
Alvaro
A
Miro-Moran
Jose A
JA
Tapia
Gines M
GM
Salido
Antonio
A
Gonzalez
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D051381:Rats; D000077185:Resveratrol; D012844:Sincalide / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology
D000975:Antioxidants; D013267:Stilbenes; D019284:Thapsigargin; D048031:JNK Mitogen-Activated Protein Kinases; D012844:Sincalide; D000077185:Resveratrol; D002118:Calcium