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Knockdown IGF-1R Triggers Viral RNA Sensors MDA-5- and RIG-I-mediated Mitochondrial Apoptosis in Colonic Cancer Cells Shu-Qing Wang,1 Xin-Feng Yu,1 Shu-Xiang Cui,2* Xian-Jun Qu1* 1Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China; 2Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China *Corresponding author: Xian Jun Qu, Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China E-mail: quxj@ccmu.edu.cn Abstract The important role of insulin-like growth factor-1 receptor (IGF-1R) in tumorogenesis has been well established. Classical model involves IGF-1R binding to IGF-1/2, following activation of PI3K/Akt signaling cascades, driving cell proliferation and apoptosis inhibition. Here, we report a new signal transduction pathway of IGF-1R in intestinal epithelium. Using heterozygous knockout mice (Igf1r+/-), we analyzed the expressions of viral RNA sensors MDA-5 and RIG-I in intestinal epithelium. Igf1r+/- mice exhibited higher MDA-5 and RIG-I than WT mice, indicating that knockdown of IGF-1R could trigger MDA5 and RIG-I. IGF-1R knockdown-triggered MDA-5 and RIG-I was further investigated in human colonic cancer cells. Increased MDA-5 and RIG-I were clearly seen in the cytoplasm in cancer cells as well as normal human colonic cells silenced IGF-1R. Notably, the upregulation of MDA5 and RIG-I was not affected by blockage of the PI3K/Akt pathway with LY294002. These results suggested a new signal transduction pathway of IGF-1R. Importantly, IGF-1R knockdown-triggered MDA-5 and RIG-I resulted in colorectal cancer apoptosis through activation of the mitochondrial pathway. These in vitro observations were evidenced in azoxymethane (AOM)/dextran sulfate sodium (DSS) colorectal cancer model of mice. In conclusion, knockdown of IGF-1R triggers viral RNA sensors MDA-5- and RIG-I-mediated mitochondrial apoptosis in cancer cells. Short title: Knockdown IGF-1R Triggers MDA5 and RIG-I Key words: IGF-1R; viral RNA sensors; MDA-5; RIG-I; mitochondrial apoptosis