The Human Host Defense Peptide LL‐37 Induces Caspaseindependent Apoptosis Via Apoptosis‐Inducing Factor And Endonuclease G in Colon Cancer Cells

Abstract

LL‐37, a human host defense peptide, plays pivotal roles in diverse biological processes, including natural immunity, inflammation and tissue repair. However, the function of this peptide in tumorigenesis remains unclear. In this study, the effect of LL‐37 on human colon cancer HCT116 cells was characterized. LL‐37 induced extensive DNA fragmentation, chromatin condensation and phosphatidylserine externalization without causing caspase activation. Moreover, these effects were not blocked by caspase inhibitors. LL‐37 induced apoptosis via downregulation of Bcl‐2 and upregulation of Bak and Bax in a p53‐dependent manner. In this connection, the pro‐apoptotic effect of LL‐37 was reversed by Bcl‐2 overexpression, genetic ablation of Bax, or p53 siRNA. LL‐ 37 also induced the upregulation and nuclear translocation of apoptosis‐inducing factor (AIF) and endonuclease G (EndoG). Knocking down of these genes by siRNAs rendered the cells resistant to LL‐37‐induced apoptosis. Above all, the pro‐apoptotic effect of LL‐37 was found to be mediated through a pertussis toxin‐sensitive Gi‐coupled receptor. Taken together, we demonstrated that LL‐37 induced caspase‐independent apoptosis via the p53‐Bcl‐2/Bak/Bax and AIF/EndoG pathways. These findings open up a novel therapeutic avenue using LL‐37 for the treatment of colon cancer.Grant support: Research Fund for the Control of Infectious Diseases, Food and Health Bureau, Hong Kong, China.