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.
Highlights
Antimicrobial peptides (AMPs), known as host defense peptides, exist in eukaryotic cells as a conserved component of the innate immune system
The cytotoxicities of FK-16 and the full-length LL-37 were initially investigated in two human colon cancer cell lines (LoVo and HCT116) by MTT assay
FK-16 displayed a better activity against colon cancer cells than LL-37
Summary
Antimicrobial peptides (AMPs), known as host defense peptides, exist in eukaryotic cells as a conserved component of the innate immune system. The selectivity of AMPs to bacterial cells relies on their cationic structures that are crucial for the interaction with negatively charged bacterial membranes [3,4]. Emerging evidence suggests that AMPs may selectively bind to cancer cells over untransformed cells because of the increased surface exposure of negatively charged phosphatidylserine in cancer [5]. Numerous AMPs of human (e.g. b-definsin, LL-37) and nonhuman (e.g. BMAP-28, lactoferricin B, magainin II, melittin, tachyplesin I) origins have been demonstrated to exert cytotoxicity on cancer cells through diverse mechanisms [6]. Bovine lactoferricin B induced mitochondrial pathway of apoptosis in human leukemia and carcinoma cell lines but not untransformed cells through generation of reactive oxygen species [7]
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