PIKE-A promotes glioblastoma growth by driving PPP flux through increasing G6PD expression mediated by phosphorylation of STAT3
PIKE-A promotes glioblastoma growth by driving PPP flux through increasing G6PD expression mediated by phosphorylation of STAT3
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PIKE-A 通过增加 STAT3 磷酸化介导的 G6PD 表达来驱动 PPP 通量，从而促进胶质母细胞瘤生长
DOI：
10.1016/j.bcp.2021.114736
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发表时间：
2021-08-24
影响因子：
5.8
通讯作者：
Zhang，Shuai
中科院分区：
文献类型：
--
作者：
Sun，Mingming;Sheng，Hao;Zhang，Shuai
能量代谢的重新编程是癌症的标志，而磷酸戊糖途径(PPP)是满足细胞生物合成和抗氧化防御需求的重要葡萄糖代谢途径。我们前期的研究表明，在细胞能量应激条件下，磷脂酰肌醇3-激酶增强子激活蛋白Akt(Pike-A)在胶质母细胞瘤细胞的存活和生长中起重要作用。然而，Pike-A在肿瘤能量代谢中的关键作用却知之甚少。在本研究中，我们发现Pike-A促进DNA生物合成、NADPH的产生和抑制ROS的产生，从而促进胶质母细胞瘤细胞的增殖和生长，抑制细胞衰老。在机制上，Pike-A与STAT3结合，并由酪氨酸激酶Fyn介导刺激其磷酸化，从而增强PPP中限速酶葡萄糖-6-磷酸脱氢酶(G6PD)的转录。最后，靶向Pike-A-G6PD轴使胶质母细胞瘤对替莫唑胺(TMZ)治疗增敏。本研究表明，STAT3是Pike-A的一个新的结合伙伴，它招募Fyn磷酸化STAT3，有助于G6PD的表达，从而促进肿瘤生长和抑制细胞衰老。因此，Pike-A/STAT3/G6PD轴将PPP与癌变紧密联系在一起，可能成为一个有前景的癌症治疗靶点。
Reprogramming of energy metabolism is a hallmark of cancer, and the pentose phosphate pathway (PPP) is a major glucose metabolic pathway important for meeting the cellular demands of biosynthesis and anti-oxidant defense. Our previous study showed that phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A) plays an important role in glioblastoma cell survival and growth under cellular energy stress condition. However, the crucial functions of PIKE-A in cancer energy metabolism are poorly understood. In the present study, we show that PIKE-A promotes DNA biosynthesis, NADPH production and inhibits reactive oxygen species (ROS) production, leading to increasing proliferation and growth of glioblastoma cell and suppressing cellular senescence. Mechanistically, PIKE-A binds to STAT3 and stimulates its phosphorylation mediated by tyrosine kinase Fyn, which enhances transcription of the rate-limitting enzyme glucose-6-phosphate dehydrogenase (G6PD) in the PPP. Finally, targeting PIKE-A-G6PD axis sensitizes glioblastoma to temozolomide (TMZ) treatment. This study reveals that STAT3 is a novel binding partner of PIKE-A which recruits Fyn to phosphorylate STAT3, contributing to the expression of G6PD, leading to promoting tumor growth and suppressing cellular senescence. Thus, the PIKE-A/STAT3/G6PD axis strongly links the PPP to carcinogenesis and may become a promising cancer therapeutic target.