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Cancer Cell. 2019 Feb 11;35(2):191-203.e8. doi: 10.1016/j.ccell.2018.12.012. Epub 2019 Jan 31.

Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation.

Author information

1
The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China; Cancer Research Institute, Guangdong Provincial Key Laboratory of Cancer Immunotherapy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
2
Cancer Research Institute, Guangdong Provincial Key Laboratory of Cancer Immunotherapy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
3
The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China; Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
4
The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China.
5
The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China. Electronic address: fxmzj2004@163.com.
6
The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518033, China; Cancer Research Institute, Guangdong Provincial Key Laboratory of Cancer Immunotherapy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA. Electronic address: yangxu@ucsd.edu.

Abstract

The tumor suppressor p53 is somatically mutated in half of all human cancers. Paradoxically, the wild-type p53 (WTp53) is often retained in certain human cancers, such as hepatocarcinoma (HCC). We discovered a physiological and oncogenic role of WTp53 in suppressing pyruvate-driven oxidative phosphorylation by inducing PUMA. PUMA inhibits mitochondrial pyruvate uptake by disrupting the oligomerization and function of mitochondrial pyruvate carrier (MPC) through PUMA-MPC interaction, which depends on IκB kinase-mediated phosphorylation of PUMA at Ser96/106. High expression levels of PUMA are correlated with decreased mitochondrial pyruvate uptake and increased glycolysis in HCCs and poor prognosis of HCC patients. These findings are instrumental for cancer drug discovery aiming at activating WTp53 or restoring WTp53 activity to p53 mutants.

KEYWORDS:

PUMA; glycolysis; mitochondria; mitochondrial pyruvate carrier; oxidative phosphorylation; p53

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