Resveratrol-induced mitochondrial dysfunction and apoptosis are associated with Ca2+ and mCICR-mediated MPT activation in HepG2 cells
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Resveratrol, a natural polyphenolic antioxidant, has been reported to possess the cancer chemopreventive potential in wide range by means of triggering tumor cells apoptosis through various pathways. It induced apoptosis through the activation of the mitochondrial pathway in some kinds of cells. In the present reports, we showed that resveratrol-induced HepG2 cell apoptosis and mitochondrial dysfunction was dependent on the induction of the mitochondrial permeability transition (MPT), because resveratrol caused the collapse of the mitochondrial membrane potential (ΔΨm) with the concomitant release of cytochrome c (Cyt.c). In addition, resveratrol induced a rapid and sustained elevation of intracellular [Ca2+], which compromised the mitochondrial ΔΨm and triggered the process of HepG2 cell apoptosis. In permeabilized HepG2 cells, we further demonstrated that the effect of the resveratrol was indeed synergistic with that of Ca2+ and Ca2+ is necessary for resveratrol-induced MPT opening. Calcium-induced calcium release from mitochondria (mCICR) played a key role in mitochondrial dysfunction and cell apoptosis: (1) mCICR inhibitor, ruthenium red (RR), prevent MPT opening and Cyt.c release; and (2) RR attenuated resveratrol-induced HepG2 cell apoptotic death. Furthermore, resveratrol promotes MPT opening by lowering Ca2+-threshold. These data suggest modifying mCICR and Ca2+ threshold to modulate MPT opening may be a potential target to control cell apoptosis induced by resveratrol.
KeywordsResveratrol Apoptosis Ca2+ Cytochrome c Mitochondrial permeability transition mCICR
The study was supported by the Grant No. 30300455 of China Natural Science Foundation. The authors express thanks for the assistance from associate professor Ande Ma and Lianbo Chen for the excellent FACS analysis.
- 6.Joe AK, Liu H, Suzui M, Vural ME, Xiao D, Weinstein IB (2002) Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Carcer Res 8(3):893–903Google Scholar
- 28.Campos CB, Paim BA, Cosso RG, Castilho RF, Rottenberg H, Vercesi AE (2006) Method for monitoring of mitochondrial cytochrome c release during cell death: immunodetection of cytochrome c by flow cytometry after selective permeabilization of the plasma membrane. Cytometry A 69(6):515–523PubMedGoogle Scholar
- 32.Whiteman M, Rose P, Siau JL, Cheung NS, Tan GS, Halliwell B, Armstrong JS (2005) Hypochlorous acid-mediated mitochondrial dysfunction and apoptosis in human hepatoma HepG2 and human fetal liver cells: role of mitochondrial permeability transition. Free Radic Biol Med 38(12):1571–1584PubMedCrossRefGoogle Scholar