Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-12, Vol.72 (24), p.6512-6523
• Main Authors: Ren, Shun X, Cheng, Alfred S L, To, Ka F, Tong, Joanna H M, Li, May S, Shen, Jing, Shen, Jin, Wong, Clover C M, Zhang, Lin, Chan, Ruby L Y, Wang, Xiao J, Ng, Simon S M, Chiu, Lawrence C M, Marquez, Victor E, Gallo, Richard L, Chan, Francis K L, Yu, Jun, Sung, Joseph J Y, Wu, William K K, Cho, Chi H
• Format: Article
• Language: English
• Subjects: Adaptive Immunity - drug effects; Adaptive Immunity - physiology; Adenocarcinoma - immunology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - prevention & control; Adult; Aged; Aged, 80 and over; Animals; Antimicrobial Cationic Peptides - metabolism; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial Cationic Peptides - physiology; Apoptosis - drug effects; Apoptosis - immunology; Case-Control Studies; Caspases - metabolism; Caspases - physiology; Cell Line, Tumor; Colonic Neoplasms - immunology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colonic Neoplasms - prevention & control; Down-Regulation - drug effects; Drug Evaluation, Preclinical; Female; HCT116 Cells; HT29 Cells; Humans; Male; Mice; Mice, Knockout; Middle Aged
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-2359

Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells.