The host defense peptide LL-37 activates the tumor-suppressing bone morphogenetic protein signaling via inhibition of proteasome in gastric cancer cells

J Cell Physiol. 2010 Apr;223(1):178-86. doi: 10.1002/jcp.22026.

Abstract

The human cathelicidin LL-37, a pleiotropic host defense peptide, is down-regulated in gastric adenocarcinomas. We therefore investigated whether this peptide suppresses gastric cancer growth. LL-37 lowered gastric cancer cell proliferation and delayed G(1)-S transition in vitro and inhibits the growth of gastric cancer xenograft in vivo. In this connection, LL-37 increased the tumor-suppressing bone morphogenetic protein (BMP) signaling, manifested as an increase in BMP4 expression and the subsequent Smad1/5 phosphorylation and the induction of p21(Waf1/Cip1). The anti-mitogenic effect, Smad1/5 phosphorylation, and p21(Waf1/Cip1) up-regulation induced by LL-37 were reversed by the knockdown of BMP receptor II. The activation of BMP signaling was paralleled by the inhibition of chymotrypsin-like and caspase-like activity of proteasome. In this regard, proteasome inhibitor MG-132 mimicked the effect of LL-37 by up-regulating BMP4 expression and Smad1/5 phosphorylation. Further analysis of clinical samples revealed that LL-37 and p21(Waf1/Cip1) mRNA expressions were both down-regulated in gastric cancer tissues and their expressions were positively correlated. Collectively, we describe for the first time that LL-37 inhibits gastric cancer cell proliferation through activation of BMP signaling via a proteasome-dependent mechanism. This unique biological activity may open up novel therapeutic avenue for the treatment of gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Aged
  • Animals
  • Antimicrobial Cationic Peptides
  • Antineoplastic Agents / pharmacology
  • Bone Morphogenetic Protein 4 / metabolism*
  • Bone Morphogenetic Protein Receptors, Type II / metabolism
  • Cathelicidins / genetics
  • Cathelicidins / metabolism*
  • Cathelicidins / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphorylation
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors
  • RNA Interference
  • RNA, Messenger / metabolism
  • Signal Transduction* / drug effects
  • Smad Proteins / metabolism
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Time Factors
  • Tumor Burden
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Antimicrobial Cationic Peptides
  • Antineoplastic Agents
  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • CDKN1A protein, human
  • Cathelicidins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Protease Inhibitors
  • Proteasome Inhibitors
  • RNA, Messenger
  • Smad Proteins
  • ropocamptide
  • Bone Morphogenetic Protein Receptors, Type II
  • Proteasome Endopeptidase Complex