Inhibition of tumor growth by U0126 is associated with induction of interferon-γ production. Int J Cancer 2015 Feb 15;136(4):771-83
Date
06/21/2014Pubmed ID
24947959DOI
10.1002/ijc.29038Scopus ID
2-s2.0-84918824827 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
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.
Author List
Ma X, Wang Q, Liu Y, Chen Y, Zhang L, Jiang M, Li X, Xiang R, Miao RQ, Duan Y, Han JMESH terms used to index this publication - Major topics in bold
Active Transport, Cell NucleusAnimals
Antineoplastic Agents
Butadienes
Carcinoma, Lewis Lung
Cell Line
Cell Nucleus
Female
Gene Expression
Interferon-gamma
Liver X Receptors
Lung
MAP Kinase Kinase Kinases
Mice, Inbred C57BL
Nitriles
Orphan Nuclear Receptors
Transcriptional Activation
Xenograft Model Antitumor Assays
