Macrophage-Associated PGK1 Phosphorylation Promotes Aerobic Glycolysis and Tumorigenesis
Macrophage-Associated PGK1 Phosphorylation Promotes Aerobic Glycolysis and Tumorigenesis
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巨噬细胞相关的 PGK1 磷酸化促进有氧糖酵解和肿瘤发生。
DOI：
10.1016/j.molcel.2018.06.023
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发表时间：
2018-07-19
期刊：
影响因子：
16
通讯作者：
Yang, Weiwei
中科院分区：
文献类型：
--
作者：
Zhang, Yajuan;Yu, Guanzhen;Yang, Weiwei
巨噬细胞是肿瘤微环境中占主导地位的白细胞群，并积极促进肿瘤的进展。然而，巨噬细胞作用的分子机制仍然知之甚少。本研究表明，极化的M2巨噬细胞通过分泌白细胞介素-6 （IL-6）增强肿瘤细胞中3-磷酸肌醇依赖蛋白激酶1 （PDPK1）介导的磷酸甘油酸激酶1 （PGK1）苏氨酸(T) 243磷酸化。这种磷酸化通过改变底物亲和力促进了pgk1催化的糖酵解反应。抑制肿瘤细胞中PGK1 T243磷酸化或PDPK1，或中和巨噬细胞来源的IL-6，可消除巨噬细胞促进的糖酵解、增殖和肿瘤发生。此外，PGK1 T243磷酸化与人多形性胶质母细胞瘤（GBM）中PDPK1激活、IL-6表达和巨噬细胞浸润相关。此外，PGK1 T243磷酸化也与人类GBM的恶性和预后相关。我们的研究结果证明了巨噬细胞通过调节肿瘤细胞代谢促进肿瘤生长的新机制，暗示通过抑制PGK1磷酸化破坏巨噬细胞和肿瘤细胞之间的联系具有治疗潜力。
Macrophages are a dominant leukocyte population in the tumor microenvironment and actively promote cancer progression. However, the molecular mechanism underlying the role of macrophages remains poorly understood. Here we show that polarized M2 macrophages enhance 3-phosphoinositide-dependent protein kinase 1 (PDPK1)-mediated phosphoglycerate kinase 1 (PGK1) threonine (T) 243 phosphorylation in tumor cells by secreting inter-leukin-6 (IL-6).This phosphorylation facilitates a PGK1-catalyzed reaction toward glycolysis by altering substrate affinity. Inhibition of PGK1 T243 phosphorylation or PDPK1 in tumor cells or neutralization of macrophage-derived IL-6 abrogates macrophage-promoted glycolysis, proliferation, and tumorigenesis. In addition, PGK1 T243 phosphorylation correlates with PDPK1 activation, IL-6 expression, and macrophage infiltration in human glioblastoma multiforme (GBM). Moreover, PGK1 T243 phosphorylation also correlates with malignance and prognosis of human GBM. Our findings demonstrate a novel mechanism of macrophage-promoted tumor growth by regulating tumor cell metabolism, implicating the therapeutic potential to disrupt the connection between macrophages and tumor cells by inhibiting PGK1 phosphorylation.