Carcinogenesis Advance Access published online on June 24, 2004
Carcinogenesis, doi:10.1093/carcin/bgh220
© 2004 by Oxford University Press
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1 Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
* To whom correspondence should be addressed. E-mail: 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 anti-tumor 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 Nterminal kinase expression vector reduced FasL expression and DNA fragmentation induced by resveratrol. However, inhibition of p38 mitogen-activated protein kinase activity bytreatment 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 Nterminal 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 JNK 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.
Revised June 15, 2004
Accepted June 15, 2004
COMMENTARY
Resveratrol induces FasL-related apoptosis through Cdc42 activation of ASK1/JNK-dependent signaling pathway in human leukemia HL-60 cells
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
6 Institute of Anatomy, School of Medicine, National Yang-Ming University, Taipei, Taiwan
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