The Host Defense Peptide LL-37 Activates the Tumor-suppressing Bone Morphogenetic Protein Signaling Via Inhibition of Proteasome in Gastric Cancer Cells
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AbstractThe 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 U. 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. J. Cell. Physiol. J. Cell. Physiol. 223: 178-186, 2010. (C) 2010 Wiley-Liss, Inc.
All Author(s) ListWu WKK, Sung JJY, To KF, Yu L, Li HT, Li ZJ, Chu KM, Yu J, Cho CH
Journal nameJournal of Cellular Physiology
Volume Number223
Issue Number1
PublisherWiley: 12 months
Pages178 - 186
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesCell Biology; CELL BIOLOGY; Physiology; PHYSIOLOGY

Last updated on 2021-18-09 at 00:14