The Protective Effects of Mcl-1 on Mitochondrial Damage and Oxidative Stress in Imiquimod-Induced Cancer Cell Death.

Simple Summary: Imiquimod (IMQ) is clinically used in the treatment of various skin malignancies. We previously showed that IMQ-induced apoptosis and autophagic cell death in skin cancer cells are ROS-dependent. Additionally, IMQ-induced apoptosis is associated with a decrease in Mcl-1 levels. However, the exact role of Mcl-1 in IMQ-induced apoptosis, including its protective mechanisms and physiological function in cancer cells, remains unclear. This study demonstrated that the overexpression of Mcl-1 or IL-6-induced Mcl-1 upregulation reversed mitochondrial dysfunction, mitochondrial fission, and mitophagy in IMQ-treated cancer cells and protected them from IMQ-induced apoptosis. These results provide significant insights supporting the role of Mcl-1 in mitochondria and suggest that it may be a potential target for cancer research and therapy. 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. [ABSTRACT FROM AUTHOR]