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Chen SJ , Bao L , Keefer K , Shanmughapriya S , Chen L , Lee J , Wang J , Zhang XQ , Hirschler-Laszkiewicz I , Merali S , Merali C , Imamura Y , Dovat S , Madesh M , Cheung JY , Wang HG , Miller BA
Transient receptor potential ion channel TRPM2 promotes AML proliferation and survival through modulation of mitochondrial function, ROS, and autophagy
Cell Death Dis. 2020 Apr 20;11(4) :247
PMID: 32312983    PMCID: PMC7170900   
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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.
Notes
2041-4889 Chen, Shu-Jen Bao, Lei Keefer, Kerry Shanmughapriya, Santhanam Chen, Longgui Lee, John Wang, JuFang Zhang, Xue-Qian Hirschler-Laszkiewicz, Iwona Merali, Salim Merali, Carmen Imamura, Yuka Dovat, Sinisa Madesh, Muniswamy Cheung, Joseph Y Wang, Hong-Gang Miller, Barbara A R01 GM109882/GM/NIGMS NIH HHS/United States R21 HL109920/HL/NHLBI NIH HHS/United States R01 HL086699/HL/NHLBI NIH HHS/United States R01 HL119306/HL/NHLBI NIH HHS/United States R01 GM117014/GM/NIGMS NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell Death Dis. 2020 Apr 20;11(4):247. doi: 10.1038/s41419-020-2454-8.