Inhibition of tumor growth by U0126 is associated with induction of interferon‐γ production

Abstract

Several MEK1/2 inhibitors have been in clinical trial evaluation for cancer treatment. Interferon-γ (IFN-γ) is a cytokine with multiple biological functions including antitumor activity. Expression of IFN-γ can be induced by liver X receptor (LXR), a ligand-activated transcription factor. However, it remains unknown if the anti-cancer action of MEK1/2 inhibitors is completed, at least in part, by activating IFN-γ expression. In this study, we determined that U0126, a MEK1/2 inhibitor, increased tumor-free and survival rates and decreased growth of inoculated Lewis lung carcinomas in wild type mice. However, the protective effects were substantially attenuated in IFN-γ deficient (IFN-γ-/-) mice. At cellular and molecular levels, MEK1/2 inhibitors increased IFN-γ protein and mRNA expression and activated natural IFN-γ promoter but not the IFN-γ promoters with mutations of the LXR responsive elements (LXREs). MEK1/2 inhibitors also enhanced formation of the LXRE-nuclear protein complexes by inducing LXR expression and nuclear translocation. Similarly, MEK1/2 siRNA inhibited phosphorylation of ERK1/2 by MEK1/2 while activated IFN-γ expression. In contrast, inhibition of LXR expression by siRNA blocked MEK1/2 inhibitors-induced IFN-γ expression. U0126 also inhibited chemicals-induced pulmonary carcinomas, which was associated with increased IFN-γ expression in the lung. Taken together, our study suggests that MEK1/2 inhibitors induce IFN-γ production in an LXR-dependent manner and the induction of IFN-γ expression can partially contribute to the anti-tumorigenic properties of U0126.