PKCα in colon cancer cells promotes M1 macrophage polarization via MKK3/6-P38 MAPK pathway.

Abstract

Tumor associated macrophages are potential targets of the immune therapy for patients with colon cancer. PKCα acts as a tumor suppressor in the intestine. However, the correlation between PKCα expressed in colon cancer cells and tumor associated macrophages polarization has never been detected. In the present study, the correlation between PKCα expression and level of M1 macrophages was evaluated in human colon cancer tissues. A xenograft mouse model of colon cancer cells with different PKCα expression level was constructed to evaluate the effect of PKCα on M1 macrophages polarization in vivo. Co-culture of colon cancer cells and differentiated macrophages was used to detect the potential interplay in vitro. PKCα regulated production of cytokines which correlated with macrophage polarization and the underlying mechanism was further explored. Our study showed that high PKCα expression in human colon cancer tissues correlated with better prognosis and high M1 macrophage content. PKCα expressed in colon cancer cells inhibited the growth of colon cancer in mice model. PKCα induced macrophages polarized to the M1-like phenotype both in vitro and in vivo. Mechanistically, PKCα targeted P38 via MKK3/6 to promote IL12 and GM-CSF expression which further enhanced M1-like macrophages polarization. In conclusion, this study provided evidence for the first time that PKCα in colon cancer cells play an anticancer action by inducing the polarization of tumor associated macrophages to M1-like phenotype in the tumor microenvironment. PKCα promoted IL12/GM-CSF-mediated M1 polarization through MKK3/6-P38 signaling pathway. Our investigation suggested that modulation of the PKCα signaling pathway might serve as a novel strategy for colon cancer therapy.

• Authors: Yang Cheng, Yun Zhu, Wanfu Xu, Jiajia Xu, Min Yang, Peiyu Chen, Junhong Zhao, Lanlan Geng, Sitang Gong
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 57 Issue 8 Pg. 1017-1029 (08 2018) ISSN: 1098-2744 [Electronic] United States
• PMID: 29637628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• PRKCA protein, human
• Protein Kinase C-alpha
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 3
• MAP Kinase Kinase 6
• MAP2K6 protein, human

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Cell Polarity
• Colonic Neoplasms (diagnosis, metabolism, pathology)
• Female
• Humans
• MAP Kinase Kinase 3 (metabolism)
• MAP Kinase Kinase 6 (metabolism)
• Macrophages (metabolism, pathology)
• Mice, Inbred BALB C
• Mice, Nude
• Prognosis
• Protein Kinase C-alpha (metabolism)
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases (metabolism)