IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth
Objective: 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. Here we aimed to determine w...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877823001709 |
| _version_ | 1797454327054336000 |
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| author | Xuemei Qiu Hongping Ye Xiaofei Li Dan Li Lu Jiang Rui Liu Zhe Zhao Dan He |
| author_facet | Xuemei Qiu Hongping Ye Xiaofei Li Dan Li Lu Jiang Rui Liu Zhe Zhao Dan He |
| author_sort | Xuemei Qiu |
| collection | DOAJ |
| description | Objective: 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. Here we aimed to determine whether and how PPP is timely tuned in response to IL-6 to support tumor growth. Methods: Protein expression was examined by immunoblot. Protein interaction was examined by immunoprecipitation. Tumor cell proliferation in in vitro culture was examined by BrdU assay and colony formation assay. Tumor cell proliferation in mouse xenograft model was examined by Ki-67 staining. Results: 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. Conclusions: 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. |
| first_indexed | 2024-03-09T15:35:41Z |
| format | Article |
| id | doaj.art-0abf313706db42fe95a151abdda75d6e |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-09T15:35:41Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-0abf313706db42fe95a151abdda75d6e2023-11-26T05:12:33ZengElsevierMolecular Metabolism2212-87782023-12-0178101836IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growthXuemei Qiu0Hongping Ye1Xiaofei Li2Dan Li3Lu Jiang4Rui Liu5Zhe Zhao6Dan He7State 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 ChinaState 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 ChinaDepartment of Oncology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, 610057, PR ChinaState 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 ChinaState 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; Corresponding author.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; Corresponding author.Nuclear Stress Medicine Center, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, 610057, PR China; Corresponding author.Department of Oncology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, Sichuan, 610057, PR China; Corresponding author.Objective: 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. Here we aimed to determine whether and how PPP is timely tuned in response to IL-6 to support tumor growth. Methods: Protein expression was examined by immunoblot. Protein interaction was examined by immunoprecipitation. Tumor cell proliferation in in vitro culture was examined by BrdU assay and colony formation assay. Tumor cell proliferation in mouse xenograft model was examined by Ki-67 staining. Results: 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. Conclusions: 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.http://www.sciencedirect.com/science/article/pii/S2212877823001709G6PDJAK2Nucleotide metabolismPentose phosphate pathwayTumorigenesis |
| spellingShingle | Xuemei Qiu Hongping Ye Xiaofei Li Dan Li Lu Jiang Rui Liu Zhe Zhao Dan He IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth Molecular Metabolism G6PD JAK2 Nucleotide metabolism Pentose phosphate pathway Tumorigenesis |
| title | IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth |
| title_full | IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth |
| title_fullStr | IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth |
| title_full_unstemmed | IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth |
| title_short | IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth |
| title_sort | il 6 jak2 dependent g6pd phosphorylation promotes nucleotide synthesis and supports tumor growth |
| topic | G6PD JAK2 Nucleotide metabolism Pentose phosphate pathway Tumorigenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2212877823001709 |
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