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

Abstract

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.

• Authors: Mingming Sun, Hao Sheng, Tingfeng Wu, Jiaqi Song, Huanran Sun, Yingzhi Wang, Jiyan Wang, Zhen Li, Huifang Zhao, Junzhen Tan, Yanping Li, Guo Chen, Qingrong Huang, Yuan Zhang, Bei Lan, Shuangping Liu, Changliang Shan, Shuai Zhang
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 192 Pg. 114736 (10 2021) ISSN: 1873-2968 [Electronic] England
• PMID: 34411567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• GTPase-Activating Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• G6PD protein, human
• Glucosephosphate Dehydrogenase
• AGAP2 protein, human
• GTP-Binding Proteins

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation (physiology)
• GTP-Binding Proteins (biosynthesis)
• GTPase-Activating Proteins (biosynthesis)
• Gene Expression Regulation, Enzymologic
• Gene Knockout Techniques (methods)
• Glioblastoma (metabolism, pathology)
• Glucosephosphate Dehydrogenase (biosynthesis, genetics)
• HEK293 Cells
• Humans
• Male
• Mice
• Mice, Nude
• Pentose Phosphate Pathway (physiology)
• Phosphorylation (physiology)
• STAT3 Transcription Factor (biosynthesis)