1.
2-D08 as a SUMOylation inhibitor induced ROS accumulation mediates apoptosis of acute myeloid leukemia cells possibly through the deSUMOylation of NOX2.
Zhou, P, Chen, X, Li, M, Tan, J, Zhang, Y, Yuan, W, Zhou, J, Wang, G
Biochemical and biophysical research communications. 2019;(4):1063-1069
Abstract
Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic malignancy with poor survival and frequent relapse. Recently, a posttranslational modification of proteins with small ubiquitin-like modifiers (SUMO) has been notably implicated in a wide spectrum of diseases, especially cancers. Ubc9, as the sole E2-conjugating enzyme in SUMOylation cascade, particularly has been associated with adverse clinical outcomes. 2-D08, a small molecular agent, functions by blocking the transfer of SUMO from the Ubc9 thioester to SUMO substrates without any effects on other individual steps in this process. However, both the effects and mechanisms of 2-D08 on AML cells are still unknown. In this study, we found that 2-D08 significantly suppressed cell viability and colony formation ability. Additionally, it induced mitochondrial-mediated apoptosis with dramatic accumulation of the reactive oxygen species (ROS), which could be almost completely rescued by the ROS scavenger N-acetylcysteine (NAC). Furthermore, we confirmed that the fatal accumulation of ROS was due to its aberrant generation instead of defective scavenging. In summary, our results suggest that 2-D08, as a specific SUMOylation inhibitor, induces ROS accumulation-mediated intrinsic apoptosis of AML cells possibly through deSUMOylation of NOX2. Therefore, 2-D08 might be a promising therapeutic agent for the treatment of AML in the future.
2.
Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment.
Chen, X, Song, M, Zhang, B, Zhang, Y
Oxidative medicine and cellular longevity. 2016;:1580967
Abstract
Reactive oxygen species (ROS) produced by cellular metabolism play an important role as signaling messengers in immune system. ROS elevated in the tumor microenvironment are associated with tumor-induced immunosuppression. T cell-based therapy has been recently approved to be effective for cancer treatment. However, T cells often become dysfunctional after reaching the tumor site. It has been reported that ROS participate extensively in T cells activation, apoptosis, and hyporesponsiveness. The sensitivity of T cells to ROS varies among different subsets. ROS can be regulated by cytokines, amino acid metabolism, and enzymatic activity. Immunosuppressive cells accumulate in the tumor microenvironment and induce apoptosis and functional suppression of T cells by producing ROS. Thus, modulating the level of ROS may be important to prolong survival of T cells and enhance their antitumor function. Combining T cell-based therapy with antioxidant treatment such as administration of ROS scavenger should be considered as a promising strategy in cancer treatment, aiming to improve antitumor T cells immunity.