PT - JOURNAL ARTICLE AU - Jie Cheng AU - Yan Huang AU - Xiaohui Zhang AU - Yue Yu AU - Wanru Zhang AU - Shumin Wu AU - Jing Jiao AU - Mei Wang AU - Linh Tran AU - Liuzhen Zhang AU - Mengyao Wang AU - Wenyu Yan AU - Yilin Wu AU - Fangtao Chi AU - Peng Jiang AU - Xinxiang Zhang AU - Hong Wu TI - TRIM21 and PHLDA3 Negatively Regulate the Cross-Talk between the PI3K/AKT Pathway and PPP Metabolism AID - 10.1101/750976 DP - 2019 Jan 01 TA - bioRxiv PG - 750976 4099 - http://biorxiv.org/content/early/2019/08/30/750976.short 4100 - http://biorxiv.org/content/early/2019/08/30/750976.full AB - PI3K/AKT signaling is known to regulate cancer metabolism but whether metabolic pathway feedbacks and regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal cross-talks between the PI3K/AKT signal and PPP branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of PPP, by inhibiting a newly identified E3 ligase TIRM21, and promotes PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of an AKT inhibitor PHLDA3. Knockout TRIM21 or PHLDA3 promotes the cross-talks and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of these reciprocal cross-talks may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.