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
Year2010
Month4
Day1
Volume Number223
Issue Number1
PublisherWiley: 12 months
Pages178 - 186
ISSN0021-9541
eISSN1097-4652
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesCell Biology; CELL BIOLOGY; Physiology; PHYSIOLOGY

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