Resveratrol analog, 3,4,5,4 '-tetrahydroxystilbene, differentially inducespro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts
Jb. Lu et al., Resveratrol analog, 3,4,5,4 '-tetrahydroxystilbene, differentially inducespro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts, CARCINOGENE, 22(2), 2001, pp. 321-328
Resveratrol, a trihydroxystilbene found in grapes and other plants, has bee
n shown to be active in inhibiting multistage carcinogenesis. Using resvera
trol as a prototype, we have synthesized a number of polyhydroxy- and polym
ethoxystilbenes and tested their anti-proliferative effect in normal and tr
ansformed human cells. Here we show that one of the resveratrol analogs, 3,
4,5,4'-tetrahydroxystilbene (R-4), specifically inhibited the growth of SV4
0 virally transformed WI38 cells (WI38VA) at 10 muM, but had no effect on n
ormal WI38 cells at even higher concentrations. R-4 also prominently induce
d apoptosis in WI38VA cells, but not in WI38 cells. RNase protection assay
showed that R-4 significantly induced the expression of p53, GADD45 and Bax
genes and concomitantly suppressed the expression of bcl-2 gene in WI38VA,
but not in WI38 cells. A large increase in p53 DNA binding activity and th
e presence of p53 in the Bax promoter binding complex suggested that p53 wa
s responsible for the Bax gene expression induced by R-4 in transformed cel
ls. Within 4 h of treatment with R-4, the Bax to bcl-2 protein ratio in WI3
8 and WI38VA cells was, respectively, 0.1 and 105, a difference of three or
ders of magnitude. While R-4 prominently induced the p53/Bax pro-apoptotic
genes, it also concomitantly suppressed the expression of Cox-2 in WI38VA c
ells, Taken together, our study suggests that the induction of p53 gene by
R-4 in transformed cells may play a key role in the differential growth inh
ibition and apoptosis of transformed cells.