title: FK-16 derived from the anticancer peptide LL-37 induces caspase-independent apoptosis and autophagic cell death in colon cancer cells.
abstract: Host immune peptides, including cathelicidins, have been reported to possess anticancer properties. We previously reported that LL-37, the only cathelicidin in humans, suppresses the development of colon cancer. In this study, the potential anticancer effect of FK-16, a fragment of LL-37 corresponding to residues 17 to 32, on cultured colon cancer cells was evaluated. FK-16 induced a unique pattern of cell death, marked by concurrent activation of caspase-independent apoptosis and autophagy. The former was mediated by the nuclear translocation of AIF and EndoG whereas the latter was characterized by enhanced expression of LC3-I/II, Atg5 and Atg7 and increased formation of LC3-positive autophagosomes. Knockdown of Atg5 or Atg7 attenuated the cytotoxicity of FK-16, indicating FK-16-induced autophagy was pro-death in nature. Mechanistically, FK-16 activated nuclear p53 to upregulate Bax and downregulate Bcl-2. Knockdown of p53, genetic ablation of Bax, or overexpression of Bcl-2 reversed FK-16-induced apoptosis and autophagy. Importantly, abolition of AIF/EndoG-dependent apoptosis enhanced FK-16-induced autophagy while abolition of autophagy augmented FK-16-induced AIF-/EndoG-dependent apoptosis. Collectively, FK-16 induces caspase-independent apoptosis and autophagy through the common p53-Bcl-2/Bax cascade in colon cancer cells. Our study also uncovered previously unknown reciprocal regulation between these two cell death pathways.
authors.affiliation: School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Shun X
authors.initials: SX
authors.lastname: Ren
authors.forename: Jin
authors.initials: J
authors.lastname: Shen
authors.forename: Alfred S L
authors.initials: AS
authors.lastname: Cheng
authors.forename: Lan
authors.initials: L
authors.lastname: Lu
authors.forename: Ruby L Y
authors.initials: RL
authors.lastname: Chan
authors.forename: Zhi J
authors.initials: ZJ
authors.lastname: Li
authors.forename: Xiao J
authors.initials: XJ
authors.lastname: Wang
authors.forename: Clover C M
authors.initials: CC
authors.lastname: Wong
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Simon S M
authors.initials: SS
authors.lastname: Ng
authors.forename: Franky L
authors.initials: FL
authors.lastname: Chan
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: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D054804:Cathelicidins / Q000494:pharmacology*; D003110:Colonic Neoplasms; D004354:Drug Screening Assays, Antitumor; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D045325:HCT116 Cells; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494829:AIFM1 protein, human; D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; C494826:BAX protein, human; D054804:Cathelicidins; C585197:LL-37 peptide (17-32), human; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020169:Caspases