Specific tumor-derived CCL2 mediated by pyruvate kinase M2 in colorectal cancer cells contributes to macrophage recruitment in tumor microenvironment

• Published in: Tumor biology Vol. 39; no. 3; p. 1010428317695962
• Main Authors: Zou, Kejian, Wang, Yaodong, Hu, Yan, Zheng, Liansheng, Xu, Wanfu, Li, Guoxin
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.03.2017; Sage Publications Ltd; IOS Press
• Subjects: Angiogenesis; Caco-2 Cells; Cell cycle; Cell Proliferation - drug effects; Cell Proliferation - genetics; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; Chemotaxis; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Culture Media, Conditioned - pharmacology; Ectopic expression; Enzyme-linked immunosorbent assay; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; HT29 Cells; Humans; Immunoglobulins; Inflammation; Intestine; Kinases; Leukocyte migration; Macrophages; Macrophages - metabolism; Macrophages - pathology; Metabolism; Monocyte chemoattractant protein 1; Phosphorylation; Polyamines; Polymerase chain reaction; Prostate; Pyruvate kinase; Pyruvate Kinase - antagonists & inhibitors; Pyruvate Kinase - genetics; Pyruvic acid; Recruitment; Signal Transduction; Transcription Factor RelA - biosynthesis; Transcription Factor RelA - genetics; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumor necrosis factor-TNF; United States > US; China; CCL2; macrophages; colorectal cancer; Pyruvate kinase M2
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1177/1010428317695962

Development of colorectal cancer has been considered as a result of imbalance of pro- and anti-inflammatory intestinal microenvironment accompanied by macrophage recruitment. Despite macrophages are implicated in remodeling tumor microenvironment, the mechanism of macrophage recruitment is not fully elucidated yet. In this study, we reported clinical association of highly expressed pyruvate kinase M2 in colorectal cancer with macrophage attraction. The conditioned medium from Caco-2 and HT-29 cells with depleted pyruvate kinase M2 dramatically reduced macrophage recruitment, which is reversed by addition of, a critical chemotaxis factor to macrophage migration, rCCL2. Silencing of endogenous pyruvate kinase M2 markedly decreased CCL2 expression and secretion by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Endogenous pyruvate kinase M2 interacted with p65 and mediated nuclear factor-κB signaling pathway and mainly regulated phosphorylation of Ser276 on p65 nuclear factor-κB. In addition, inhibition of macrophage recruitment caused by pyruvate kinase M2 silencing was rescued by ectopic expression of p65. Interestingly, pyruvate kinase M2 highly expressed in colorectal cancer tissue, which is correction with macrophage distribution. Taken together, we revealed a novel mechanism of pyruvate kinase M2 in promoting colorectal cancer progression by recruitment of macrophages through p65 nuclear factor-κB–mediated expression of CCL2.