There is evidence for defects in the mechanisms that allow the activation of p53 in many of the
cancers that retain wild-type p53. Reactivation of p53 has been suggested to be an effective strategy for
cancer therapy in wild-type p53-retained
tumor cells. In the present study, we attempted to reactivate p53 in HepG2 retaining wild-type p53 by
quercetin, an ubiquitous bioactive plant
flavonoid. Our results show that
quercetin inhibited the proliferation of HepG2 cells through the induction of cell cycle arrest and apoptosis, as characterized by the cell cycle distribution and DNA fragmentation. Molecular data revealed that
quercetin induced p53 phosphorylation and total p53
protein, but that it did not up-regulate p53
mRNA at the transcription level. Consequently,
quercetin stimulated p21 expression and suppressed
cyclin D1 expression in favor of cell cycle arrest.
Quercetin also increased the ratio of Bax/Bcl-2 in favor of apoptosis with such treatment. Interestingly,
quercetin inhibited p53 ubiquitination and extended the half-life (t(1/2)) of p53 from 74 to 184 min.
Quercetin also inhibited p53 mRNA degradation at the post-transcription stage. Silencing p53 with p53
small interfering RNA (
siRNA) significantly abrogated the p53-dependent gene expression and apoptotic induction. Taken together, our data demonstrate that
quercetin stabilized p53 at both the
mRNA and
protein levels to reactivate p53-dependent cell cycle arrest and apoptosis in HepG2 cells.