Abstract
Oncogenic activation of Ras/MEK downregulates the expression of interferon regulatory factor 1 (IRF1), which is a prerequisite for oncolytic viruses to replicate in cancer cells [1]. Moreover, restoration of IRF1 expression is essential to induce apoptosis of cancer cells treated with a MEK inhibitor [2]. However, the molecular mechanisms that underlie IRF1 downregulation by Ras/MEK remain unclear. In this study, we determined whether Ras/MEK activation modulates IRF1 expression at its translational level. MEK inhibition increased the activity of IRF1 promoter construct in Ras transformed NIH3T3 cells and wild type MEF, but not in IRF1 deficient MEF, indicating that IRF1 protein is required for the transcriptional activation of IRF1. By conducting reporter analysis using IRF1 5’- and 3’- UTR constructs, we determined that cis elements on 5’- and 3’-UTR of IRF1 mRNA are not involved in the IRF1 regulation by Ras/MEK. We further compared the recruitment of ribosomes to IRF1 mRNA in RasV12 cells treated with or without the MEK inhibitor by conducting polysome analysis. No difference was observed in the polysomal distribution of IRF1 mRNA between RasV12 cells treated with and without the MEK inhibitor. These results suggest that regulation of IRF1 translation is independent of IRF1 downregulation by Ras/MEK.
Highlights
Oncolytic viruses preferentially replicate within cancer cells, leading to destruction of cancer cells while keeping the normal cells unharmed
We demonstrated that mitogen-activated protein kinase/extracellular signal regulated kinases (ERK) kinase (MEK) inhibition restored interferon regulatory factor 1 (IRF1) expression in human cancer cells and that the level of IRF1 expression defines the sensitivity of cancer cells to certain oncolytic viruses
To determine which IRF1 transcription or translation is the primary target of Ras/MEK, we examined whether Ras/ MEK modulates IRF1 transcription in the absence of IRF1 protein (Fig 2)
Summary
Oncolytic viruses preferentially replicate within cancer cells, leading to destruction of cancer cells while keeping the normal cells unharmed. Oncolytic viruses exploit tumor-specific molecular changes in cancer cells for their replication, such as p53 deficiency [3], oncogenic Ras activation [3], defects in the type I interferon (IFN)-induced antiviral response [4] and viral receptors uniquely expressed on cancer cells [5]. Noser et al (2007) reported that the inhibition of Ras-Raf-MEK-ERK pathway in human cancer cell lines restored antiviral responses induced by IFN [7]. These studies clearly demonstrated that the tumor-specific molecular changes exploited by oncolytic viruses, oncogenic Ras activation and defects in the type I IFN, are connected.
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