The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, 100871, China.
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
Nat Commun. 2020 Apr 20;11(1):1880. doi: 10.1038/s41467-020-15819-3.
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.
PI3K/AKT 信号通路已知可调节癌症代谢，但代谢反馈是否调节 PI3K/AKT 通路尚不清楚。在这里，我们证明了 PI3K/AKT 信号与戊糖磷酸途径（PPP）分支代谢途径之间存在重要的相互交流。PI3K/AKT 激活通过抑制新发现的 E3 连接酶 TIRM21 稳定 PPP 的限速酶 G6PD，促进 PPP。反过来，PPP 代谢物通过阻断 AKT 抑制剂 PHLDA3 的表达，进一步加强 AKT 激活并促进癌症代谢重编程。TRIM21 或 PHLDA3 的缺失会促进串扰和细胞增殖。重要的是，PTEN 缺失的人类癌细胞和体内小鼠模型对 PPP 抑制剂敏感，这表明即使在存在组成性激活的 PI3K 通路的情况下，PPP 对于维持 AKT 激活也很重要。我们的研究表明，阻断这种相互交流机制可能对具有 PTEN 缺失或 PI3K/AKT 激活的癌症具有治疗益处。
