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.