Butein activates p53 in hepatocellular carcinoma cells via blocking MDM2-mediated ubiquitination
Authors Zhou Y, Wang K, Zhou N, Huang T, Zhu J, Li J
Received 17 December 2017
Accepted for publication 9 February 2018
Published 6 April 2018 Volume 2018:11 Pages 2007—2015
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Yao Dai
Yuanfeng Zhou,1,2 Kuifeng Wang,2 Ni Zhou,2 Tingting Huang,2 Jiansheng Zhu,2 Jicheng Li1
1Institute of Cell Biology, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, People’s Republic of China
Introduction: In this study, we aimed to investigate the effect of butein on p53 in hepatocellular carcinoma (HCC) cells and the related molecular mechanisms by which p53 was activated.
Methods: MTS assay and clonogenic survival assay were used to examine the antitumor activity of butein in vitro. Reporter gene assay was adopted to evaluate p53 transcriptional activity. Flow cytometry and western blotting were performed to study apoptosis induction and protein expression respectively. Xenograft model was applied to determine the in vivo efficacy and the expression of p53 in tumor tissue was detected by immunohistochemistry.
Results: HCC cell proliferation and clonogenic survival were significantly inhibited after butein treatment. With the activation of cleaved-PARP and capsase-3, butein induced apoptosis in HCC cells in a dose-dependent manner. The transcriptional activity of p53 was substantially promoted by butein, and the expression of p53-targeted gene was increased accordingly. Mechanism studies demonstrated that the interaction between MDM2 and p53 was blocked by butein and MDM2-mediated p53 ubiquitination was substantially decreased. Short-hairpin RNA experiment results showed that the sensitivity of HCC cells to butein was substantially impaired after p53 was knocked down and butein-induced apoptosis was dramatically decreased. In vivo experiments validated substantial antitumor efficacy of butein against HepG2 xenograft growth, and the expression of p53 in butein-treated tumor tissue was significantly increased.
Conclusion: Butein demonstrated potent antitumor activities in HCC by activating p53, and butein or its analogs had therapeutic potential for HCC management.
Keywords: butein, cell apoptosis, hepatocellular carcinoma, MDM2, natural product, p53, ubiquitination
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