TRIM21 and PHLDA3 Negatively Regulate the Cross-Talk between the PI3K/AKT Pathway and PPP Metabolism [article]

Hong Wu, Jie Cheng, Yan Huang, Xiaohui Zhang, Yue Yu, Wanru Zhang, Mei Wang, Liuzhen Zhang, Mengyao Wang, Wenyu Yan, Yilin Wu, Shumin Wu (+5 others)
<span title="2019-08-30">2019</span> <i title="Cold Spring Harbor Laboratory"> bioRxiv </i> &nbsp; <span class="release-stage" >pre-print</span>
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
more &raquo; ... ogramming 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.
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