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

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.