title: 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.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China; College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Xingzhe
authors.initials: X
authors.lastname: Ma
authors.forename: Qixue
authors.initials: Q
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Yuanli
authors.initials: Y
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Meixiu
authors.initials: M
authors.lastname: Jiang
authors.forename: Xiaoju
authors.initials: X
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.forename: Robert Q
authors.initials: RQ
authors.lastname: Miao
authors.forename: Yajun
authors.initials: Y
authors.lastname: Duan
authors.forename: Jihong
authors.initials: J
authors.lastname: Han
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D000071518:Liver X Receptors; D008168:Lung / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000494:pharmacology*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D000071518:Liver X Receptors; D009570:Nitriles; D057093:Orphan Nuclear Receptors; C113580:U 0126; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases
keywords: ERK1/2; IFN-γ; LLC1; LXR; MEK1/2; carcinogens