Macrophage-Associated PGK1 Phosphorylation Promotes Aerobic Glycolysis and Tumorigenesis.

Abstract

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 interleukin-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.

• Authors: Yajuan Zhang, Guanzhen Yu, Huiying Chu, Xiongjun Wang, Lingling Xiong, Guoqing Cai, Ruilong Liu, Hong Gao, Bangbao Tao, Wenfeng Li, Guohui Li, Ji Liang, Weiwei Yang
• Journal: Molecular cell (Mol Cell) Vol. 71 Issue 2 Pg. 201-215.e7 (07 19 2018) ISSN: 1097-4164 [Electronic] United States
• PMID: 30029001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• 3-Phosphoinositide-Dependent Protein Kinases
• PDPK1 protein, human
• PGK1 protein, human
• Phosphoglycerate Kinase

Topics

• 3-Phosphoinositide-Dependent Protein Kinases (genetics, metabolism)
• Animals
• Brain Neoplasms (genetics, metabolism, pathology)
• Carcinogenesis (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic (metabolism, pathology)
• Female
• Glioblastoma (genetics, metabolism, pathology)
• Glycolysis
• Humans
• Macrophages (metabolism, pathology)
• Mice
• Mice, Nude
• Multiple Myeloma (genetics, metabolism, pathology)
• Phosphoglycerate Kinase (genetics, metabolism)
• Phosphorylation
• Prognosis
• Tumor Microenvironment