title: Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer.
abstract: 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.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Shun X
authors.initials: SX
authors.lastname: Ren
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.forename: Ka F
authors.initials: KF
authors.lastname: To
authors.forename: Joanna H M
authors.initials: JH
authors.lastname: Tong
authors.forename: May S
authors.initials: MS
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Jin
authors.initials: J
authors.lastname: Shen
authors.forename: Clover C M
authors.initials: CC
authors.lastname: Wong
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Ruby L Y
authors.initials: RL
authors.lastname: Chan
authors.forename: Xiao J
authors.initials: XJ
authors.lastname: Wang
authors.forename: Simon S M
authors.initials: SS
authors.lastname: Ng
authors.forename: Lawrence C M
authors.initials: LC
authors.lastname: Chiu
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Francis K L
authors.initials: FK
authors.lastname: Chan
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
authors.forename: Chi H
authors.initials: CH
authors.lastname: Cho
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000502:physiology; D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D020169:Caspases; D054804:Cathelicidins