Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells.
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.
Tanigawa
Shunsuke
S
Department of Biochemistry and Applied Biosciences, United Graduate School of Agricultural Sciences, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan.
Fujii
Makoto
M
Hou
De-Xing
DX
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology; D010766:Phosphorylation; D011794:Quercetin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D011794:Quercetin