Statins Inhibit Toll-Like Receptor 4–Mediated Growth of Human Esophageal Adenocarcinoma Cells

Abstract

BackgroundEsophageal adenocarcinoma (EAC) is a lethal malignancy with poor prognosis. Pharmacologic inhibitors of inflammation, such as statins, have been shown to decrease the risk of development and progression of esophageal cancer, but the mechanism of this protection is unclear. The objective of this study was to elucidate the effect of statins on toll-like receptor 4-mediated–proliferation of human EAC cells and identify the mechanism responsible for these observed effects. MethodsHuman EAC cells (OE33 and FLO1) were treated with simvastatin or atorvastatin for increasing doses and time periods. Toll-like receptor 4 (TLR4) expression was assessed. Cells were pretreated with statin followed by lipopolysaccharide (LPS). Cell proliferation and expression of signaling proteins were evaluated. FLO1 cells were injected into the flank of nude mice. Mice received intraperitoneal injections of simvastatin, atorvastatin, or control solution and tumor volume was measured. ResultsOE33 and FLO1 cells demonstrated decreased TLR4 expression after treatment with simvastatin or atorvastatin for 8 h (P < 0.05). LPS increased proliferation, whereas pretreatment with statin abolished this response (P < 0.05). Statins decreased expression and activation of LPS-induced signaling proteins, including MyD88, TRAF6, Akt, and NF-κB (P < 0.05). Mice receiving daily statin injections demonstrated smaller tumors than control mice (P < 0.001 at day 33). ConclusionsTreatment of EAC cells with simvastatin or atorvastatin decreases TLR4-mediated proliferation and in vivo tumor growth. Decreased TLR4 expression and subsequent reduction in MyD88-dependent signaling could be a mechanism by which statins act to reduce tumor growth rates.