The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells

Abstract

Cancer development can be viewed as dysregulated repair. Antimicrobial peptides (AMPs) are effector molecules of the innate immune system with direct antimicrobial activity. Beside this host defence function several AMPs play a role in the regulation of inflammation and tissue repair. The aim of the present study was to investigate whether the human cathelicidin AMP LL-37/hCAP-18 is involved in the biology of lung cancer. Human cancer cell lines were found to express the human cathelicidin LL-37/hCAP-18 mRNA and peptide at different levels. Immunohistochemistry of human lung cancers showed that the peptide is expressed mostly in adenocarcinoma and squamous cell carcinoma. Application of exogenous LL-37 at low concentrations of 5ng/ml to cancer cell lines increased proliferation and growth of anchorage-independent colonies. At the molecular level, LL-37 induced phosphorylation of the epidermal growth factor receptor (EGFR) and activation of downstream MAP kinase signalling pathways. Lung cancer cell lines that stably overexpress the peptide by means of a doxycycline-regulated promoter system also showed a faster growth. When these cell lines were injected subcutaneously into nude mice, cathelicidin overexpression resulted in increased tumourigenicity and the formation of significantly larger tumours. In conclusion, cathelicidin is expressed in human lung cancers. The peptide activates tumour cells resulting in increased cell growth in vitro and in an animal model. The host defence peptide cathelicidin LL-37/hCAP-18 acts as growth factor for human lung cancer.