The human host defense peptide cathelicidin induces AIF‐ and EndoG‐mediated cell death in colon cancer cells

Abstract

Human cathelicidin (LL‐37) is implicated in cancer development. In this study, we demonstrate that LL‐37 was substantially downregulated in primary tumor tissues of 58 out of 60 cases of colon cancer as revealed by immunohistochemistry. Functional characterization indicates that LL‐37 reduced cell viability and induced apoptosis in cultured colon cancer cells as evidenced by increased phosphatidylserine externalization and DNA fragmentation. The pro‐apoptotic action of LL‐37 was caspase‐independent as neither LL‐37 induced caspase activation nor its action could be blocked by a pan‐caspase inhibitor. LL‐37‐induced apoptosis was accompanied by the nuclear translocation of apoptosis‐inducing factor (AIF) and endonuclease G (EndoG), knockdown of either of which reversed the pro‐apoptotic action of LL‐37. These molecular events were preceded by p53 activation and p53‐dependent upregulation of Bax and Bak and downregulation of Bcl‐2 in LL‐37‐treated colon cancer cells, in which knockdown or genetic ablation of Bax, Bak or p53 or overexpression of Bcl‐2 abolished LL‐37‐induced nuclear translocation of AIF and EndoG and apoptosis. The pro‐apoptotic effect of LL‐37 was mediated by a pertussis toxin‐sensitive G‐protein‐coupled receptor. Taken together, LL‐37 activates the p53‐Bax/Bak axis to stimulate AIF‐ and EndoG‐mediated caspase‐independent apoptosis in colon cancer cells. These findings may shed light on the novel tumor suppressive function of LL‐37 in colon cancer.