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PIKE-A promotes glioblastoma growth by driving PPP flux through increasing G6PD expression mediated by phosphorylation of STAT3.

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机构： [1]State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China [2]Biomedical Translational Research Institute, Jinan University, Guangzhou, Guangdong 510632, China [3]Department of Neurosurgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, China [4]School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China [5]Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining, Shandong 272067, China [6]Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou 510632, China [7]School of Life Sciences, Ludong University, Yantai, Shandong 264025, China [8]Qingyuan People’s Hospital, Qingyuan, Guangdong 511518, China [9]Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China [10]Department of Pathology, Medical School, Dalian University, Dalian, Liaoning 116622, China

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关键词： PIKE-A Phosphorylation Glioblastoma G6PD STAT3 Fyn

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Reprogramming of energy metabolism is a hallmarkofcancer, 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.Copyright © 2021 Elsevier Inc. All rights reserved.

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大类 | 2 区

医学

小类 | 1 区药学

最新[2025]版：

大类 | 2 区医学

小类 | 2 区药学

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第一作者机构： [1]State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China

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PIKE-A promotes glioblastoma growth by driving PPP flux through increasing G6PD expression mediated by phosphorylation of STAT3.

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