Suppression of IFN-Induced Transcription Underlies IFN Defects Generated by Activated Ras/MEK in Human Cancer Cells

Abstract

Certain oncolytic viruses exploit activated Ras signaling in order to replicate in cancer cells. Constitutive activation of the Ras/MEK pathway is known to suppress the effectiveness of the interferon (IFN) antiviral response, which may contribute to Ras-dependent viral oncolysis. Here, we identified 10 human cancer cell lines (out of 16) with increased sensitivity to the anti-viral effects of IFN-α after treatment with the MEK inhibitor U0126, suggesting that the Ras/MEK pathway underlies their reduced sensitivity to IFN. To determine how Ras/MEK suppresses the IFN response in these cells, we used DNA microarrays to compare IFN-induced transcription in IFN-sensitive SKOV3 cells, moderately resistant HT1080 cells, and HT1080 cells treated with U0126. We found that 267 genes were induced by IFN in SKOV3 cells, while only 98 genes were induced in HT1080 cells at the same time point. Furthermore, the expression of a distinct subset of IFN inducible genes, that included RIGI, GBP2, IFIT2, BTN3A3, MAP2, MMP7 and STAT2, was restored or increased in HT1080 cells when the cells were co-treated with U0126 and IFN. Bioinformatic analysis of the biological processes represented by these genes revealed increased representation of genes involved in the anti-viral response, regulation of apoptosis, cell differentiation and metabolism. Furthermore, introduction of constitutively active Ras into IFN sensitive SKOV3 cells reduced their IFN sensitivity and ability to activate IFN-induced transcription. This work demonstrates for the first time that activated Ras/MEK in human cancer cells induces downregulation of a specific subset of IFN-inducible genes.

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

“…This contrasts with results using transformed human colonic cell lines that respond to rotavirus infection and poly(I:C) with type I IFN-β at the transcript and protein levels, and type I IFN regulates ISG induction in these cells (16,42,72). Transformed cells often have significant deficits in their response to pathogens, including in IFN signaling pathways (73,74). It seems likely that this critical difference in IFN responses to rotavirus and poly(I:C) between immortalized cell lines and nontransformed HIE cultures is partially attributed to their transformation status.…”

Decreased IFIT2 Expression Promotes Gastric Cancer Progression and Predicts Poor Prognosis of the Patients

“…Lai et al have also reported that the decreased IFIT2 expression in human oral squamous cells can activate the PKC signaling pathway and promote the epithelial-mesenchymal transition (EMT) of the cancer cells [7]. Christian et al have also shown that the down-regulation of IFIT2 can be regulated by the activated Ras/MEK signaling pathway [19]. Lai et al have also found that the IFIT2 depletion can up-regulate the TNF-α secretion and further lead to angiogenesis and metastasis of OSCC cells [20].…”

The Importance of Physiologically Relevant Cell Lines for Studying Virus–Host Interactions

“…When murine embryonic fibroblasts (MEFs) were Ras-transformed in the presence of IRF1, it appeared to trigger p53-dependent growth-arrest and apoptosis; consequently, IRF1 −/− MEFs were more easily transformed [54,55]. Furthermore, it has been observed that Ras-transformed cells have down-regulated IRF1, which explains the reduced antiviral responsiveness of these cells [56,57]. Thus, IRF1 acts as a tumor suppressor during Ras-transformation and is selected against during tumorigenesis.…”