TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

Jie Cheng, Yan Huang, Xiaohui Zhang, Yue Yu, Shumin Wu, Jing Jiao, Linh Tran, Wanru Zhang, Ran Liu, Liuzhen Zhang, Mei Wang, Mengyao Wang, Wenyu Yan, Yilin Wu, Fangtao Chi, Peng Jiang, Xinxiang Zhang and Hong Wu ()
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Jie Cheng: Peking University
Yan Huang: Peking University
Xiaohui Zhang: Peking University
Yue Yu: Peking University
Shumin Wu: University of California, Los Angeles
Jing Jiao: University of California, Los Angeles
Linh Tran: University of California, Los Angeles
Wanru Zhang: Peking University
Ran Liu: Peking University
Liuzhen Zhang: Peking University
Mei Wang: Peking University
Mengyao Wang: Peking University
Wenyu Yan: Peking University
Yilin Wu: Peking University
Fangtao Chi: University of California, Los Angeles
Peng Jiang: Tsinghua University
Xinxiang Zhang: Peking University
Hong Wu: Peking University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.

Date: 2020
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DOI: 10.1038/s41467-020-15819-3

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