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Synergistic roles of p53 and HIF1α in human renal cell carcinoma-cell apoptosis responding to the inhibition of mTOR and MDM2 signaling pathways

Authors Liu Q, Shen H, Lin J, Xu X, Ji Z, Han X, Shang D, Yang P

Received 18 May 2015

Accepted for publication 6 September 2015

Published 18 February 2016 Volume 2016:10 Pages 745—755

DOI https://doi.org/10.2147/DDDT.S88779

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Mohsin Khan

Peer reviewer comments 3

Editor who approved publication: Professor Wei Duan

Qing-jun Liu,* Hong-liang Shen,* Jun Lin, Xiu-hong Xu, Zheng-guo Ji, Xiao Han, Dong-hao Shang, Pei-qian Yang

Department of Urology Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China

*These authors contributed equally to this work

Introduction: mTOR and MDM2 signaling pathways are frequently deregulated in cancer development, and inhibition of mTOR or MDM2 independently enhances carcinoma-cell apoptosis. However, responses to mTOR and MDM2 antagonists in renal cell carcinoma (RCC) remain unknown.
Materials and methods: A498 cells treated with MDM2 antagonist MI-319 and/or mTOR inhibitor rapamycin were employed in the present study. Cell apoptosis and Western blot analysis were performed.
Results and conclusion: We found that the MDM2 inhibitor MI-319 induced RCC cell apoptosis mainly dependent on p53 overexpression, while the mTOR antagonist rapamycin promoted RCC cell apoptosis primarily through upregulation of HIF1α expression. Importantly, strong synergistic effects of MI-319 and rapamycin combinations at relatively low concentrations on RCC cell apoptosis were observed. Depletion of p53 or HIF1α impaired both antagonist-elicited apoptoses to differential extents, corresponding to their expression changes responding to chemical treatments, and double knockdown of p53 and HIF1α remarkably hindered MI-319- or rapamycin-induced apoptosis, suggesting that both p53 and HIF1α are involved in MDM2 or mTOR antagonist-induced apoptosis. Collectively, we propose that concurrent activation of p53 and HIF1α may effectively result in cancer-cell apoptosis, and that combined MDM2 antagonists and mTOR inhibitors may be useful in RCC therapy.

Keywords: renal cell carcinoma, mTOR, MDM2, p53, HIF1α, apoptosis

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