Leucine leucine-37 uses formyl peptide receptor-like 1 to activate signal transduction pathways, stimulate oncogenic gene expression, and enhance the invasiveness of ovarian cancer cells

Mol Cancer Res. 2009 Jun;7(6):907-15. doi: 10.1158/1541-7786.MCR-08-0326. Epub 2009 Jun 2.

Abstract

Emerging evidence suggests that the antimicrobial peptide, leucine leucine-37 (LL-37), could play a role in the progression of solid tumors. LL-37 is expressed as the COOH terminus of human cationic antimicrobial protein-18 (hCAP-18) in ovarian, breast, and lung cancers. Previous studies have shown that the addition of LL-37 to various cancer cell lines in vitro stimulates proliferation, migration, and invasion. Similarly, overexpression of hCAP-18/LL-37 in vivo accelerates tumor growth. However, the receptor or receptors through which these processes are mediated have not been thoroughly examined. In the present study, expression of formyl peptide receptor-like 1 (FPRL1) was confirmed on ovarian cancer cells. Proliferation assays indicated that LL-37 does not signal through a G protein-coupled receptor, such as FPRL1, to promote cancer cell growth. By contrast, FPRL1 was required for LL-37-induced invasion through Matrigel. The peptide stimulated mitogen-activated protein kinase and Janus-activated kinase/signal transducers and activators of transcription signaling cascades and led to the significant activation of several transcription factors, through both FPRL1-dependent and FPRL1-independent pathways. Likewise, expression of some LL-37-stimulated genes was attenuated by the inhibition of FPRL1. Increased expression of CXCL10, EGF, and PDGF-BB as well as other soluble factors was confirmed from conditioned medium of LL-37-treated cells. Taken together, these data suggest that LL-37 potentiates a more aggressive behavior from ovarian cancer cells through its interaction with FPRL1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antimicrobial Cationic Peptides / biosynthesis
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / metabolism
  • Antimicrobial Cationic Peptides / pharmacology*
  • Cathelicidins
  • Cell Line, Tumor
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Neoplasm Invasiveness
  • Oncogenes*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • RNA, Small Interfering / genetics
  • Receptors, Formyl Peptide / antagonists & inhibitors
  • Receptors, Formyl Peptide / biosynthesis
  • Receptors, Formyl Peptide / genetics
  • Receptors, Formyl Peptide / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Lipoxin / antagonists & inhibitors
  • Receptors, Lipoxin / biosynthesis
  • Receptors, Lipoxin / genetics
  • Receptors, Lipoxin / metabolism*
  • Recombinant Proteins / pharmacology

Substances

  • Antimicrobial Cationic Peptides
  • FPR2 protein, human
  • RNA, Small Interfering
  • Receptors, Formyl Peptide
  • Receptors, G-Protein-Coupled
  • Receptors, Lipoxin
  • Recombinant Proteins
  • Cathelicidins