Department of Surgery, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 600 Yishan Road, 200233 Shanghai, China.
Department of Surgery, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, 600 Yishan Road, 200233 Shanghai, China.
Biomed Pharmacother. 2017 Nov;95:1574-1579. doi: 10.1016/j.biopha.2017.09.087. Epub 2017 Oct 6.
Colorectal cancer (CRC) cells undergo apoptosis in the presence of the small-molecule inhibitor ABT-263 by up-regulating antiapoptotic Bcl-2 family members. However, the resistance to ABT-263 gradually developed in most solid tumors due to its low affinity to Mcl-1. Here, we found the BET-Bromodomain inhibitor JQ1, when combined with ABT-263, synergistically reduced Mcl-1 protein level, induced apoptosis, and decreased cell viability in the CRC HCT-15, HT-29 and SW620 cells. The subsequent mechanism study revealed that a pathway of c-Myc/miR-1271-5p/Noxa/Mcl-1 underlies the synergistic effect of such combination treatment. We discovered that miR-1271-5p, the key mediator for the synergistic effect, is transcriptionally activated by c-Myc, and binds to the 3'-UTR of noxa to inhibit its protein production. The combination treatment of JQ1 and ABT-263 inhibited c-Myc protein level and also c-Myc-driven expression of miR-1271-5p, subsequently increased the protein level of Noxa, and finally promotes the degradation of Mcl-1. Our findings provide an alternative strategy to resolve the resistance during treatment of CRC by JQ1, and also discovered a novel miR-1271-5p-dependent regulatory mechanism for gene expression of noxa.
结直肠癌（CRC）细胞在小分子抑制剂 ABT-263 的存在下通过上调抗凋亡 Bcl-2 家族成员而发生细胞凋亡。然而，由于其对 Mcl-1 的亲和力低，大多数实体瘤对 ABT-263 的耐药性逐渐发展。在这里，我们发现 BET-Bromodomain 抑制剂 JQ1 与 ABT-263 联合使用时，可协同降低 CRC HCT-15、HT-29 和 SW620 细胞中的 Mcl-1 蛋白水平，诱导细胞凋亡并降低细胞活力。随后的机制研究表明，c-Myc/miR-1271-5p/Noxa/Mcl-1 通路是这种联合治疗协同作用的基础。我们发现，miR-1271-5p 是协同作用的关键介质，由 c-Myc 转录激活，并与 Noxa 的 3'-UTR 结合以抑制其蛋白质产生。JQ1 和 ABT-263 的联合治疗抑制了 c-Myc 蛋白水平，也抑制了 c-Myc 驱动的 miR-1271-5p 的表达，随后增加了 Noxa 的蛋白水平，并最终促进了 Mcl-1 的降解。我们的研究结果为通过 JQ1 解决 CRC 治疗中的耐药性提供了一种替代策略，同时也发现了 Noxa 基因表达的 miR-1271-5p 依赖性新调节机制。
