BET抑制剂JQ1在结肠癌细胞中通过GSK3下调c-FLIP诱导凋亡的机制研究

以JQ1为代表的BET蛋白抑制剂具有重要的抗肿瘤作用，其抗癌机制复杂，目前已用于多种恶性肿瘤的治疗，但是JQ1在结肠癌治疗中的应用报道较少。c-FLIP是细胞中抗凋亡的重要因子，能够促进结肠癌等肿瘤的发展，我们的前期工作发现，JQ1能够下调包括结肠癌在内的许多肿瘤细胞中c-FLIP的蛋白水平，其机制尚不清楚。在预实验中，使用JQ1处理结肠癌细胞后，其p-GSK3水平增加，结合既往的研究结果GSK3对c-FLIP具有调控作用，我们提出“JQ1通过抑制GSK3促进结肠癌细胞内c-FLIP的泛素化降解，进而诱导肿瘤细胞凋亡”这一假说。我们将在细胞水平及动物模型上进一步证实JQ1对c-FLIP的下调作用及其对结肠癌细胞增殖、凋亡的影响，通过抑制及过表达GSK3、干预相关信号通路的的方法，初步阐明JQ1促进c-FLIP降解的作用机制，为研究JQ1的在结肠癌中的抗肿瘤作用提供新的思路。

JQ1 and other BET inhibitors have emerged as a promising cancer therapeutic strategy which exert their anticancer activity by complicated mechanisms, and some of them have reached clinical use for cancer treatment. However, there are not many studies about JQ1 used for colon cancer. c-FLIP is an important anti-apoptosis protein which promotes colon cancer and other malignant tumor development. Our previous study shows JQ1 could downregulate c-FLIP in many tumor cells including colon cancer, but the mechanisms have not been fully elucidated. Our preliminary experiment has revealed p-GSK3 in colon cancer cells increased after treated with JQ1. In consideration of previous finding that GSK3 could modulate c-FLIP, we propose the hypothesis：JQ1 downregulates c-FLIP through inhibition of GSK3 in colon cancer, and promotes tumor cell apoptosis by increasing c-FLIP degradation. We will test the effect of JQ1 on c-FLIP and tumor cell proliferation and apoptosis in cell lines and animal models. Moreover, we will uncover the mechanisms of JQ1 promoting c-FLIP degradation by inhibition or overexpression of GSK3 and intervention of related signaling pathway. In summary, our findings would provide a novel strategy for colon cancer treatment with JQ1.