2. Academic Validation
  3. IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth

IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth

  • Mol Metab. 2023 Nov 8:101836. doi: 10.1016/j.molmet.2023.101836.
Xuemei Qiu 1,  Hongping Ye 1,  Xiaofei Li 2,  Dan Li 1,  Lu Jiang 3,  Rui Liu 4,  Zhe Zhao 5,  Dan He 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, PR China.
  • 2 Department of Oncology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, 610057, PR China.
  • 3 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, PR China. Electronic address: jianglu@scu.edu.cn.
  • 4 State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, PR China. Electronic address: liurui_scu@hotmail.com.
  • 5 Nuclear Stress Medicine Center, The Second Affiliated Hospital of Chengdu Medical College Nuclear Industry 416 Hospital, Chengdu, Sichuan, 610057, PR China. Electronic address: 18803743168@163.com.
  • 6 Department of Oncology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, 610057, PR China. Electronic address: hd_baby81@163.com.
PMID: 37949355 DOI: 10.1016/j.molmet.2023.101836
Abstract

Tumor cells hijack inflammatory mechanisms to promote their own growth. IL-6 is one of the major cytokines, and is frequently upregulated in tumors. The pentose phosphate pathway (PPP) generates the indispensable building blocks to produce various nucleotides. However, whether and how PPP is timely tuned in response to IL-6 to support tumor growth remains largely unknown. Here we show that the metabolic flux of PPP and enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD) is rapidly induced under IL-6 treatment, without obvious changes in G6PD expression level. Mechanistically, Janus kinase 2 (JAK2) phosphorylates G6PD Y437 under IL-6 treatment, which accentuates G6PD enzymatic activity by promoting G6PD binding with its substrate G6P. Further, JAK2-dependent G6PD Y437 phosphorylation is required for IL-6-induced nucleotide biosynthesis and tumor cell proliferation, and is associated with the progression of oral squamous cell carcinoma. Our findings report a new mechanism implicated in the crosstalk between tumor cells and inflammatory microenvironment, by which JAK2-dependent activation of G6PD governs nucleotide synthesis to support tumor cell proliferation, thereby highlighting its value as a potential anti-tumor target.

Keywords

G6PD; JAK2; Nucleotide metabolism; Pentose phosphate pathway; Tumorigenesis.

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