Activation of FXR Suppresses Esophageal Squamous Cell Carcinoma Through Antagonizing ERK1/2 Signaling Pathway.

Abstract

IntroductionFarnesoid X receptor (FXR), a member of nuclear receptors, functionally regulates bile acid, glucose and lipid homeostasis. It is also worth noting that FXR plays a suppressor role in cancer and inflammation. However, the contribution of FXR to esophageal squamous cell carcinoma (ESCC) remains unknown.MethodsThe role of FXR activation in ESCC progression was evaluated in ESCC cell lines KYSE150 and EC109 in vitro and BALB-C nude mice in vivo. In vitro, FXR synthetic ligand GW4064 was used to detect the effects on ESCC cell proliferation, migration, apoptosis and cell cycles. To assess the effects of GW4064 on ESCC development in vivo, a xenograft tumor model was constructed. And ERK1/2 activity was evaluated by immunoblot analysis.ResultsFXR synthetic ligand GW4064 impaired esophageal squamous cell carcinoma (ESCC) proliferation and migration, induced apoptosis and cell cycle arrest in vitro, accompanied by inhibition of some inflammatory genes and promotion of pro-apoptotic genes. We then found that FXR activation decreased the phosphorylation levels of ERK1/2 induced by tumor necrosis factor-α (TNF-α) in ESCC cells. Consistent with these results, GW4064 suppressed ESCC tumorigenesis in a xenograft model and suppressed the phosphorylation of ERK1/2 in tumors.DiscussionThese findings identify that activating FXR may serve as a promising therapy or adjuvant therapeutic tool for controlling ESCC development.