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

Several MEK1/2 inhibitors have been in clinical trial evaluation for cancer treatment. Interferon- (IFN-) is a cytokine with multiple biological functions including antitumor activity. Expression of IFN- 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- 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- deficient (IFN-(-/-)) mice. At cellular and molecular levels, MEK1/2 inhibitors increased IFN- protein and mRNA expression and activated natural IFN- promoter but not the IFN- 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- expression. In contrast, inhibition of LXR expression by siRNA blocked MEK1/2 inhibitors-induced IFN- expression. U0126 also inhibited chemicals-induced pulmonary carcinomas, which was associated with increased IFN- expression in the lung. Taken together, our study suggests that MEK1/2 inhibitors induce IFN- production in an LXR-dependent manner and the induction of IFN- expression can partially contribute to the anti-tumorigenic properties of U0126. What's new? Both MEK1/2 inhibitors and interferon- (IFN-) have anti-tumorigenic activity. In this study, the authors found that the MEK1/2 inhibitor U0126 decreases growth of chemically induced pulmonary carcinomas, and increases tumor-free and survival rates in mice inoculated Lewis lung carcinomas. The authors also conclude that this anti-tumorigenic action of U0126 is due, in part, to its activation of IFN- production, via enhanced activity of liver X receptor (LXR).