2.4.2 Reactive oxygen species (ROS)
Sudjit Luanpitpong et al 63 first confirmed a subpopulation of CSC (cancer stem cells) that was regulated by using ROS (reactive oxygen species) in MCL cell lines and patient-derived primary cells and inversely correlated with the sensitivity of bortezomib (BTZ). ROS are necessary signaling molecules in the tumor microenvironment. O2- has a vast inhibitory impact on CSC-like cells, while H2O2 has an extensive enriching and apoptosis-inhibiting impact on CSC-like cells. Mcl-1 and Zeb-1 (also regarded as TCF8) are effective targets of O2- and H2O2. Using CRISPR/Cas9 gene editing technology, the expression of Mcl-1 was inhibited, and the expression of Zeb-1 was decreased, while the expression of TCF8 was increased. It was found that intracellular ROS levels increased significantly after Mcl-1 gene silencing, and Mcl-1 is a critical target gene of O2 and has a regulatory role in CSC-like cells, suggesting that ROS has an impact in BTZ-induced apoptosis and CSC-like cells can resist BTZ-induced apoptosis by apoptosis-regulating protein Mcl-1. What’s more, mitochondrial membrane potential is also an important factor in the protective impact of the mitochondrial antioxidant system on BTZ-induced apoptosis.