Carcinogenesis Advance Access originally published online on June 24, 2004
Carcinogenesis 2005 26(1):1-10; doi:10.1093/carcin/bgh220
Carcinogenesis vol.26 no.1 © Oxford University Press 2005; all rights reserved.
Resveratrol induces FasL-related apoptosis through Cdc42 activation of ASK1/JNK-dependent signaling pathway in human leukemia HL-60 cells
Jen-Liang Su1,*,
Ming-Tsan Lin2,*,
Chih-Chen Hong3,
Cheng-Chi Chang1,
Shine-Gwo Shiah4,
Cheng-Wen Wu4,
Szu-Ta Chen5,
Yat-Pang Chau6 and
Min-Liang Kuo1,7
1 Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, 2 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, 3 Division of Cancer Research, National Health Research Institutes, Taipei 115, Taiwan, 4 President's Laboratory, National Health Research Institute, Taipei 115, Taiwan, 5 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan and 6 Institute of Anatomy, School of Medicine, National Yang-Ming University, Taipei, Taiwan
7 To whom correspondence should be addressed Email: toxkml{at}ha.mc.ntu.edu.tw
Trans-resveratrol, a phytoalexin found at high levels in grapes and in grape products such as red wine, has been shown to prevent carcinogenesis or antitumor growth in murine models. Here we dissect the detailed signaling pathway involved in resveratrol-induced apoptosis. Our data showed that treatment with resveratrol-induced activation of apoptosis signal-regulating kinase 1, a mitogen-activated protein kinase kinase kinase, in turn, activated the downstream kinases c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, but not extracellular signal-regulated kinase. Transfection with a dominant-negative c-Jun N-terminal kinase expression vector reduced FasL expression and DNA fragmentation induced by resveratrol. However, inhibition of p38 mitogen-activated protein kinase activity by treatment with SB203580 (p38 mitogen-activated protein kinase specific inhibitor) or expression of mutant p38 mitogen-activated protein kinase expression vector did not alter the apoptosis and FasL expression in response to resveratrol. Furthermore, genetic inhibition of apoptosis signal-regulating kinase 1 signaling inhibited not only the activation of c-Jun N-terminal kinase, but also the expression of FasL and apoptosis. Similarly, over-expression of wild-type apoptosis signal-regulating kinase 1 strengthened the resveratrol-induced c-Jun N-terminal kinase activation, FasL expression and subsequent apoptosis. These results suggest the possible involvement of apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase signaling in the regulation of FasL expression and subsequent apoptosis induced by resveratrol in HL-60 cells. Resveratrol also activated the small GTP-binding protein Cdc42, rather than other members such as RhoA or Rac1. Expression of a mutant Cdc42 (N17 Cdc42) dramatically reduced resveratrol-induced c-Jun N-terminal kinase activity, FasL expression and apoptotic cell death. These results showed that resveratrol induced apoptosis through the Cdc42/apoptosis signal-regulating kinase 1/c-Jun N-terminal kinase/FasL signaling cascade in HL-60 cells.
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