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TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism.
Nature Communications ( IF 14.7 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41467-020-15819-3 Jie Cheng 1 , Yan Huang 1 , Xiaohui Zhang 2 , Yue Yu 2 , Shumin Wu 3 , Jing Jiao 3 , Linh Tran 3 , Wanru Zhang 1 , Ran Liu 1 , Liuzhen Zhang 1 , Mei Wang 1 , Mengyao Wang 1 , Wenyu Yan 1 , Yilin Wu 1 , Fangtao Chi 4 , Peng Jiang 5 , Xinxiang Zhang 2 , Hong Wu 1, 3
Nature Communications ( IF 14.7 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41467-020-15819-3 Jie Cheng 1 , Yan Huang 1 , Xiaohui Zhang 2 , Yue Yu 2 , Shumin Wu 3 , Jing Jiao 3 , Linh Tran 3 , Wanru Zhang 1 , Ran Liu 1 , Liuzhen Zhang 1 , Mei Wang 1 , Mengyao Wang 1 , Wenyu Yan 1 , Yilin Wu 1 , Fangtao Chi 4 , Peng Jiang 5 , Xinxiang Zhang 2 , Hong Wu 1, 3
Affiliation
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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.
中文翻译：
TRIM21和PHLDA3负调节PI3K / AKT途径与PPP代谢之间的串扰。
已知PI3K / AKT信号调节癌症代谢，但是尚不清楚代谢反馈是否调节PI3K / AKT途径。在这里，我们证明了PI3K / AKT信号和戊糖磷酸途径（PPP）分支代谢途径之间的重要相互影响。PI3K / AKT激活通过抑制新鉴定的E3连接酶TIRM21并促进PPP来稳定PPP的限速酶G6PD。PPP代谢产物进而通过阻断AKT抑制剂PHLDA3的表达来增强AKT活化并进一步促进癌症代谢重编程。TRIM21或PHLDA3的敲除促进串扰和细胞增殖。重要的是，没有PTEN的人类癌细胞和体内鼠模型对抗PPP治疗敏感，这表明即使在存在组成型激活的PI3K途径的情况下，PPP在维持AKT激活中的重要性。我们的研究表明，阻断这种相互的串扰机制可能会对PTEN丢失或PI3K / AKT激活的癌症具有治疗益处。
更新日期：2020-04-24
中文翻译：
TRIM21和PHLDA3负调节PI3K / AKT途径与PPP代谢之间的串扰。
已知PI3K / AKT信号调节癌症代谢，但是尚不清楚代谢反馈是否调节PI3K / AKT途径。在这里，我们证明了PI3K / AKT信号和戊糖磷酸途径（PPP）分支代谢途径之间的重要相互影响。PI3K / AKT激活通过抑制新鉴定的E3连接酶TIRM21并促进PPP来稳定PPP的限速酶G6PD。PPP代谢产物进而通过阻断AKT抑制剂PHLDA3的表达来增强AKT活化并进一步促进癌症代谢重编程。TRIM21或PHLDA3的敲除促进串扰和细胞增殖。重要的是，没有PTEN的人类癌细胞和体内鼠模型对抗PPP治疗敏感，这表明即使在存在组成型激活的PI3K途径的情况下，PPP在维持AKT激活中的重要性。我们的研究表明，阻断这种相互的串扰机制可能会对PTEN丢失或PI3K / AKT激活的癌症具有治疗益处。
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