野生型 p53 通过诱导 PUMA 依赖性的氧化磷酸化抑制促进癌症代谢转换。
Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation.
机构信息
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.
Cancer Research Institute, Guangdong Provincial Key Laboratory of Cancer Immunotherapy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
出版信息
Cancer Cell. 2019 Feb 11;35(2):191-203.e8. doi: 10.1016/j.ccell.2018.12.012. Epub 2019 Jan 31.
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.
抑癌基因 p53 在半数的人类癌症中发生体细胞突变。矛盾的是，野生型 p53（WTp53）在某些人类癌症中经常被保留，如肝癌（HCC）。我们发现 WTp53 通过诱导 PUMA 抑制丙酮酸驱动的氧化磷酸化具有生理和致癌作用。PUMA 通过 PUMA-MPC 相互作用破坏线粒体丙酮酸载体（MPC）的寡聚化和功能来抑制线粒体丙酮酸摄取，这依赖于 IκB 激酶介导的 PUMA 在 Ser96/106 上的磷酸化。在 HCC 中，PUMA 的高表达水平与线粒体丙酮酸摄取减少和糖酵解增加相关，并且与 HCC 患者的预后不良相关。这些发现对于旨在激活 WTp53 或恢复 p53 突变体的 WTp53 活性的癌症药物发现具有重要意义。
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