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.

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

“…4A) [14]. FK-16, a fragment of residues 17 to 32 of LL-37, upregulated the expression of LC3-I/II, Atg5 and Atg7, enabling formation of LC3-positive autophagosomes [15]. These observations show that FK-16 triggers caspase-independent apoptosis and autophagy through the p53-Bcl-2/Bax signaling in colon cancer cells (Fig.…”

Enhanced antitumor effects by docetaxel/LL37-loaded thermosensitive hydrogel nanoparticles in peritoneal carcinomatosis of colorectal cancer

“…They showed that the expression of LL37 was remarkably downregulated in human colon cancer tissues, whereas exogenous LL37 induced apoptotic cell death in cultured colon cancer cells. 1,2 However, LL37 strongly reduced cell viability at high doses (20-60 μmol/L), and it did not show any effect at low doses (0.5-10 μmol/L) or even stimulate cell proliferation in other cancer types. 1 The combination of LL37 and an anticancer chemotherapy drug was considered to achieve higher antitumor efficacy and minimize the emergence of resistance.…”

“…1,2 However, LL37 strongly reduced cell viability at high doses (20-60 μmol/L), and it did not show any effect at low doses (0.5-10 μmol/L) or even stimulate cell proliferation in other cancer types. 1 The combination of LL37 and an anticancer chemotherapy drug was considered to achieve higher antitumor efficacy and minimize the emergence of resistance. Docetaxel (Doc), a semisynthetic analog of paclitaxel, is a widely used anticancer agent that has been used for the treatment of various human malignancies.…”

“…1 To test the hypothesis that combination of LL37 and Doc might enhance the antitumor activity of Doc for colorectal peritoneal carcinomatosis, in this study we encapsulated the Doc and LL37 in NPs to prepare combination Doc+LL37 NPs. However, conventional intravenous therapy showed severe systemic toxicity, which remarkably limited the intensity of chemotherapy and diminished the life quality of patients.…”

Estudo sobre a produção e a ação dos peptídeos antimicrobianos em camundongos submetidos à tolerância ao LPS e à sepse por ligadura e punção cecal

“…Entre seus efeitos no sistema imune, elas participam da secreção de citocinas por macrófagos murinos (Pinheiro da Silva et al, 2009a), alteram respostas quimiotáticas (Yang et al, 2000b), apoptose (Ren et al, 2012) ativação de inflamassoma (Salzer et al, 2014) e fagocitose (Wang et al, 2014 Barlow et al, 2011), como também por impedir a sinalização do complexo receptor/ligante em células dendríticas e macrófagos (Di Nardo et al,2007;Brown et al, 2011). Isso resultaria em menor produção de citocinas quando LPS e LL-37 estão presentes simultaneamente.…”