Transient receptor potential ion channel TRPM2 promotes AML proliferation and survival through modulation of mitochondrial function, ROS, and autophagy

Abstract

Transient receptor potential melastatin 2 (TRPM2) ion channel has an essential function in maintaining cell survival following oxidant injury. Here, we show that TRPM2 is highly expressed in acute myeloid leukemia (AML). The role of TRPM2 in AML was studied following depletion with CRISPR/Cas9 technology in U937 cells. In in vitro experiments and in xenografts, depletion of TRPM2 in AML inhibited leukemia proliferation, and doxorubicin sensitivity was increased. Mitochondrial function including oxygen consumption rate and ATP production was reduced, impairing cellular bioenergetics. Mitochondrial membrane potential and mitochondrial calcium uptake were significantly decreased in depleted cells. Mitochondrial reactive oxygen species (ROS) were significantly increased, and Nrf2 was decreased, reducing the antioxidant response. In TRPM2-depleted cells, ULK1, Atg7, and Atg5 protein levels were decreased, leading to autophagy inhibition. Consistently, ATF4 and CREB, two master transcription factors for autophagosome biogenesis, were reduced in TRPM2-depleted cells. In addition, Atg13 and FIP200, which are known to stabilize ULK1 protein, were decreased. Reconstitution with TRPM2 fully restored proliferation, viability, and autophagy; ATF4 and CREB fully restored proliferation and viability but only partially restored autophagy. TRPM2 expression reduced the elevated ROS found in depleted cells. These data show that TRPM2 has an important role in AML proliferation and survival through regulation of key transcription factors and target genes involved in mitochondrial function, bioenergetics, the antioxidant response, and autophagy. Targeting TRPM2 may represent a novel therapeutic approach to inhibit myeloid leukemia growth and enhance susceptibility to chemotherapeutic agents through multiple pathways.

Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function

“…Mitochondrial calcium uptake significantly improved depleted cells and regulated cytosolic calcium signal [27,28]. Our results indicated that increased Ca 2+ levels of mitochondrial significantly upregulate the expression of PGC-1, NRF-1, and mtTFA, is one of the signals mediating mitochondrial biogenesis.…”

Electroacupuncture pretreatment alleviates myocardial injury through regulating mitochondrial function

“…Mitochondrial calcium uptake signi cantly improved depleted cells and regulated cytosolic calcium signal [27,28]. Our results indicated that increased Ca 2+ levels of mitochondrial signi cantly upregulate the expression of PGC-1, NRF-1, and mtTFA, is one of the signals mediating mitochondrial biogenesis.…”

Modifications of Plasma Membrane Organization in Cancer Cells for Targeted Therapy

“…Transient receptor potential melastatin 2 (TRPM2) belongs to non-selective cation channels. Its role in regulating cancer growth and metastasis was confirmed by many studies [129,130]. On the other hand, selective downregulation of TRPM2 via shRNA results in the proliferation decrease and apoptosis promotion in gastric and lung cancer cells.…”