Mitochondria, vital organelles that generate ATP, determine cell fate. Dysfunctional and damaged mitochondria are fragmented and removed through mitophagy, a mitochondrial quality control mechanism. The FDA-approved drug IMQ, a synthetic agonist of Toll-like receptor 7, exhibits antitumor activity against various skin malignancies. We previously reported that IMQ promptly reduced the level of the antiapoptotic Mcl-1 protein and that Mcl-1 overexpression attenuated IMQ-triggered apoptosis in skin cancer cells. Furthermore, IMQ profoundly disrupted mitochondrial function, promoted mitochondrial fragmentation, induced mitophagy, and caused cell death by generating high levels of ROS. However, whether Mcl-1 protects mitochondria from IMQ treatment is still unknown. In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development.
线粒体作为产生ATP的关键细胞器，决定着细胞命运。功能失调和受损的线粒体通过线粒体自噬——一种线粒体质量控制机制——被裂解清除。美国食品药品监督管理局批准的药物IMQ是一种Toll样受体7的合成激动剂，对多种皮肤恶性肿瘤具有抗肿瘤活性。我们先前报道过，IMQ能迅速降低抗凋亡蛋白Mcl-1的水平，而过表达Mcl-1可减弱IMQ在皮肤癌细胞中引发的凋亡。此外，IMQ通过产生高水平的活性氧，显著破坏线粒体功能，促进线粒体裂解，诱导线粒体自噬，并导致细胞死亡。然而，Mcl-1是否能保护线粒体免受IMQ处理的影响尚不清楚。在本研究中，我们证明Mcl-1过表达诱导了对IMQ诱导的凋亡的抵抗，并减少了IMQ诱导的癌细胞中活性氧的产生和氧化应激。Mcl-1过表达维持了线粒体功能和完整性，并防止了IMQ处理的癌细胞中线粒体自噬的发生。此外，IL-6通过增加Mcl-1表达和减弱IMQ诱导的线粒体裂解来保护细胞免受IMQ诱导的凋亡。Mcl-1过表达改善了IMQ诱导的活性氧生成和线粒体裂解，从而增加了线粒体稳定性，最终减弱了IMQ诱导的细胞死亡。研究Mcl-1在线粒体中的作用是开发癌症治疗策略的潜在途径。
肿瘤(癌症)患者之家