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

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

doi:10.1016/j.bcp.2021.114736

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

Biochem Pharmacol. 2021 Oct:192:114736. doi: 10.1016/j.bcp.2021.114736. Epub 2021 Aug 16.

Authors

Mingming Sun¹, Hao Sheng², Tingfeng Wu³, Jiaqi Song¹, Huanran Sun¹, Yingzhi Wang¹, Jiyan Wang¹, Zhen Li², Huifang Zhao⁴, Junzhen Tan⁴, Yanping Li⁵, Guo Chen⁶, Qingrong Huang⁷, Yuan Zhang⁸, Bei Lan⁹, Shuangping Liu¹⁰, Changliang Shan¹¹, Shuai Zhang¹²

Affiliations

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. Electronic address: liushuangping@dlu.edu.cn.
¹¹ State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China. Electronic address: changliangshan@nankai.edu.cn.
¹² School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. Electronic address: shuaizhang@tjutcm.edu.cn.

PMID: 34411567
DOI: 10.1016/j.bcp.2021.114736

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.

Keywords: Fyn; G6PD; Glioblastoma; PIKE-A; Phosphorylation; STAT3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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*
Glioblastoma / pathology
Glucosephosphate Dehydrogenase / biosynthesis*
Glucosephosphate Dehydrogenase / genetics
HEK293 Cells
Humans
Male
Mice
Mice, Nude
Pentose Phosphate Pathway / physiology*
Phosphorylation / physiology
STAT3 Transcription Factor / biosynthesis*

Substances

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