肿瘤细胞劫持炎症机制以促进自身生长。 IL-6 是主要细胞因子之一，在肿瘤中经常上调。磷酸戊糖途径 (PPP) 生成生产各种核苷酸所必需的构建模块。然而，PPP 是否以及如何及时调整以响应 IL-6 以支持肿瘤生长仍然很大程度上未知。在这里，我们发现，在IL-6处理下，PPP的代谢通量和葡萄糖-6-磷酸脱氢酶（G6PD）的酶活性迅速诱导，而G6PD表达水平没有明显变化。从机制上讲，Janus 激酶 2 (JAK2) 在 IL-6 处理下磷酸化 G6PD Y437，从而通过促进 G6PD 与其底物 G6P 结合来增强 G6PD 酶活性。此外，JAK2依赖性G6PD Y437磷酸化是IL-6诱导的核苷酸生物合成和肿瘤细胞增殖所必需的，并且与口腔鳞状细胞癌的进展相关。我们的研究结果报告了一种与肿瘤细胞和炎症微环境之间的串扰有关的新机制，通过该机制，JAK2 依赖性 G6PD 激活控制核苷酸合成以支持肿瘤细胞增殖，从而凸显其作为潜在抗肿瘤靶点的价值。版权所有 © 2023作者。由 Elsevier GmbH 出版。保留所有权利。

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.Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.