Cell Death Dis: Ion Channel TRPM2 Promotes AML Cell Proliferation by Regulating Mitochondrial Function, ROS and Autophagy

The study found that levels of reactive oxygen (ROS) increased in acute myeloid leukemia (AML)Mitochondria are the main source of ROS, which damages tissue simply through protein oxidation, lipid peroxidation, and DNA oxidation and mutationIn malignant tumor cells, a moderate increase in ROS levels can promote the proliferation and metastasis of tumor cells, while excessive elevation can lead to cell deathTRPM2 ion channels play an important role in the maintenance of cell survival after oxidation damageThe study found that TRPM2 had a high expression level in AMLResearchers used CRISPR/Cas9 technology to knock out TRPM2 in U937 cells to study its role in AMLin vitro and transplant tumor experiments, trpm2 deficiency inhibits the proliferation of leukemia cells in AML, and increases sensitivity to doxorubicin, while mitochondrial function, including oxygen consumption and ATP production, decreases and impairs the biological function of cellsIn knockout cells, the mitochondria's membrane potential and the calitomic calcium intake were significantly reduced, accompanied by a significant increase in mitochondrial ROS levels, a decrease in Nrf2 expression levels, and a decrease in the antioxidant response of the cellsin TRPM2 knockout cells, protein levels in ULK1, Atg7 and Atg5 were reduced and cell autophagy was inhibitedSimilarly, in the cells missing from TRPM2, the expression levels of attofle 4 and CREB, the two main transcription factors associated with autophagy, decreasedIn addition, the expression levels of Atg13 and FIP200, which improve the stability of the ULK1 protein, were also reducedSupplementing TRPM2 can fully restore the cell's proliferation, survival and autophagy capability, while supplementing ATF4 and CREB can fully restore the cell's ability to multiply and survive, but only partially restore the autophagy capacity of the cellAdding TRPM2 to the knockout cells can reduce elevated ROS levels in the cellsthe above results show that TRPM2 can play an important role in cell proliferation and survival of acute myeloid leukemia by regulating key transcription factors and target genes involving mitochondrial function, biological function, antioxidant reaction and cell autophagyTargeting TRPM2 may be a new treatment that not only inhibits the growth of myeloid leukemia, but also enhances patients' sensitivity to chemotherapy drugs by regulating multiple pathways