Cathelicidin, an antimicrobial peptide produced by macrophages, promotes colon cancer by activating the Wnt/β-catenin pathway

Dong Li; Wenfang Liu; Xuan Wang; Junlu Wu; Wenqiang Quan; Yiwen Yao; Robert Bals; Shurong Ji; Kaiyin Wu; Jia Guo; Haiying Wan

doi:10.18632/oncotarget.2845

Cathelicidin, an antimicrobial peptide produced by macrophages, promotes colon cancer by activating the Wnt/β-catenin pathway

Oncotarget. 2015 Feb 20;6(5):2939-50. doi: 10.18632/oncotarget.2845.

Authors

Dong Li¹, Wenfang Liu², Xuan Wang³, Junlu Wu¹, Wenqiang Quan¹, Yiwen Yao¹, Robert Bals⁴, Shurong Ji², Kaiyin Wu⁵, Jia Guo⁶, Haiying Wan¹

Affiliations

¹ Department of Clinical Laboratory, Tongji Hospital of Tongji University, 200065 Shanghai, China.
² Department of General Surgery, Tongji Hospital of Tongji University, 200065 Shanghai, China.
³ Department of Pharmacy, Putuo People's Hospital, 200060 Shanghai, China.
⁴ Department of Internal Medicine V - Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, 66424 Homburg, Germany.
⁵ Institute of Pathology, Charité University Hospital, 12200 Berlin, Germany.
⁶ Tongji University Suzhou Institute, 215000 Suzhou, China.

Abstract

Here we found that levels of cathelicidin, an antimicrobial peptide, were increased in colon cancer tissues compared to noncancerous tissues. Importantly, cathelicidin was mainly expressed in immune cells. Contact with tumor cells caused macrophages to secrete cathelicidin. Neutralization of cathelicidin, in vivo, significantly reduced the engraftment of macrophages into colon tumors, as well as proliferation of tumor cells, resulting in an inhibition of tumor growth. Furthermore, treatment with cathelicidin neutralizing antibody de-activated the Wnt/β-catenin signaling pathway in tumor cells both in vivo and in vitro. Cathelicidin activated Wnt/β-catenin signaling by inducing phosphorylation of PTEN, leading to activation of PI3K/Akt signaling and subsequent phosphorylation of GSK3β, resulting in stabilization and nuclear translocation of β-catenin. These data indicate that cathelicidin, expressed by immune cells in the tumor microenvironment, promotes colon cancer growth through activation of the PTEN/PI3K/Akt and Wnt/β-catenin signaling pathways.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / pharmacology
Antimicrobial Cationic Peptides / antagonists & inhibitors
Antimicrobial Cationic Peptides / immunology
Antimicrobial Cationic Peptides / metabolism*
Antimicrobial Cationic Peptides / pharmacology
Case-Control Studies
Cathelicidins
Cell Proliferation
Cell Transformation, Neoplastic / metabolism*
Cell Transformation, Neoplastic / pathology
Coculture Techniques
Colitis / complications*
Colitis / metabolism
Colonic Neoplasms / etiology*
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Disease Models, Animal
Female
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
HCT116 Cells
Humans
Macrophages / drug effects
Macrophages / metabolism*
Mice, Inbred C57BL
PTEN Phosphohydrolase / metabolism
Paracrine Communication* / drug effects
Phosphatidylinositol 3-Kinase / metabolism
Phosphorylation
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
Time Factors
Transfection
Tumor Burden
Tumor Microenvironment
U937 Cells
Wnt Signaling Pathway* / drug effects
beta Catenin / metabolism*

Substances

Antibodies, Neutralizing
Antimicrobial Cationic Peptides
CTNNB1 protein, human
CTNNB1 protein, mouse
beta Catenin
Phosphatidylinositol 3-Kinase
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Proto-Oncogene Proteins c-akt
Glycogen Synthase Kinase 3
PTEN Phosphohydrolase
PTEN protein, human
Cathelicidins