Enhanced antitumor activity of vitamin C via p53 in cancer cells.
Ascorbate is an important natural antioxidant that can selectively kill cancer cells at pharmacological concentrations. Despite its benefit, it is quite difficult to predict the antitumor effects of ascorbate, because the relative cytotoxicity of ascorbate differs between cancer cell lines. Therefore, it is essential to examine the basis for this fundamental disagreement. Because p53 is activated by DNA-damaging stress and then regulates various cellular conditions, we hypothesized that p53 can sensitize cancer cells to ascorbate. Using isogenic cancer cells, we observed that the presence of p53 can affect ascorbate cytotoxicity, and also reactivation of p53 can make cancer cells sensitive to ascorbate. p53-dependent enhancement of ascorbate cytotoxicity is caused by increased reactive oxygen species generation via a differentially regulated p53 transcriptional network. We also found that transcriptionally activated p53 was derived from MDM2 ubiquitination by ascorbate and subsequently its signaling network renders cancer cells more susceptible to oxidative stress. Similar to the p53 effect on in vitro ascorbate cytotoxicity, inhibition of tumor growth is also stronger in p53-expressing tumors than in p53-deficient ones in vivo. This is the first observation that ascorbate cytotoxicity is positively related to p53 expression, activating its transcriptional network to worsen intracellular oxidative stress and consequently enhancing its cytotoxicity. Based on our study, reactivation of p53 may help to achieve more consistent cytotoxic effects of ascorbate in cancer therapies.
Research Center for Women's Diseases, Department of Biological Sciences, Korea.
Jinsun
J
Kim
Soon-Duck
SD
Lee
Boogi
B
Chang
Dong-Hoon
DH
Jin
Sam-Il
SI
Jung
Mee-Young
MY
Park
Youngsoo
Y
Han
Young
Y
Yang
Keun
K
Il Kim
Jong-Seok
JS
Lim
Young-Sook
YS
Kang
Myeong-Sok
MS
Lee
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001205:Ascorbic Acid / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D000975:Antioxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D051736:Proto-Oncogene Proteins c-mdm2; D001205:Ascorbic Acid