DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts.
DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts.
复制标题
DOI：
10.1016/j.cell.2015.07.056
复制
发表时间：
2015-08-27
期刊：
影响因子：
64.5
通讯作者：
De Carvalho DD
中科院分区：
文献类型：
--
作者：
Roulois D;Loo Yau H;Singhania R;Wang Y;Danesh A;Shen SY;Han H;Liang G;Jones PA;Pugh TJ;O'Brien C;De Carvalho DD
DNA去甲基化剂已经通过未知的作用机制显示出临床抗肿瘤功效。结合结直肠癌细胞的实验和生物信息学分析，我们证明了低剂量5-AZA-CdR通过诱导病毒拟态靶向结直肠癌起始细胞（CIC）。这与至少部分来源于内源性逆转录病毒元件的dsRNA的诱导、MDA 5/MAVS RNA识别途径的激活和IRF 7的下游激活有关。事实上，通过单独敲除MDA 5、MAVS或IRF 7破坏病毒识别途径，抑制了5-AZA-CdR靶向结肠直肠CIC的能力，并显著降低了5-AZA-CdR的长期生长效应。此外，将dsRNA转染到CIC中可以模拟5-AZA-CdR的作用。一起;我们的结果代表了对DNA去甲基化剂抗肿瘤机制理解的重大转变，并强调了MDA 5/MAVS/IRF 7途径作为抗CIC的潜在药物靶点。抗肿瘤DNA去甲基化剂通过诱导内源性dsRNA的转录而起作用，内源性dsRNA激活病毒识别和干扰素应答途径。这种抗病毒应答减少结直肠癌起始细胞的增殖。
DNA demethylating agents have shown clinical anti-tumor efficacy via an unknown mechanism of action. Using a combination of experimental and bioinformatics analysis in colorectal cancer cells, we demonstrate that low-dose 5-AZA-CdR targets colorectal cancer initiating cells (CICs) by inducing viral mimicry. This is associated with induction of dsRNAs derived at least in part from endogenous retroviral elements, activation of the MDA5/MAVS RNA recognition pathway and downstream activation of IRF7. Indeed, disruption of virus recognition pathways, by individually knocking down MDA5, MAVS or IRF7, inhibits the ability of 5-AZA-CdR to target colorectal CICs and significantly decreases 5-AZA-CdR long-term growth effects. Moreover, transfection of dsRNA into CICs can mimic the effects of 5-AZA-CdR. Together; our results represent a major shift in understanding the antitumor mechanisms of DNA-demethylating agents and highlight the MDA5/MAVS/IRF7 pathway as a potentially druggable target against CICs. Antitumor DNA demethylating agents act by inducing transcription of endogenous dsRNAs that activate the viral recognition and interferon response pathway This anti-viral response reduces the proliferation of colorectal cancer initiating cells.