Suppression of UCP2 alleviatesleukemogenesis by enhancingbranched-chain amino acids-inducedoxidative stress via activating the PI3K/AKT/mTOR signaling pathwayOA
Although the cellular role of uncoupling protein 2(UCP2)in tumorigenesis has been reported in various solid tumor models,its role in leukemogenesis remains elusive.Herein,we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance,suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia.Mechanistically,in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival,accompanied by the disruption of mitochondrial homeostasis.Interestingly,RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids(BCAAs),which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway.Additionally,the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2.More importantly,supplementation of BCAA enhanced the anti-tumor activity of genipin,a selective inhibitor that targets UCP2,resulting in significantly reduced acute myeloid leukemia blasts,increased mouse survival,and magnified oxidative stress.Taken together,our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.
Agida Okohi Innocent;Yajie Shen;Yixuan Gao;Ruixin Sun;Kasimujiang aximujiang;Zizhen Xu;Jinke Cheng;Jiao Ma
Department of Biochemistry and Molecular Cell Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaState Key Laboratory of Genetic Engineering,School of Life Sciences and Huashan Hospital,Shanghai Engineering Research Center of Industrial Microorganisms,Fudan University,Shanghai 200438,ChinaDepartment of Biochemistry and Molecular Cell Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaDepartment of Biochemistry and Molecular Cell Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China Department of Laboratory Medicine,College of Health Science and Technology,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaDepartment of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Xinjiang Medical University,Urumqi,Xinjiang 710061,ChinaDepartment of Laboratory Medicine,College of Health Science and Technology,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaDepartment of Biochemistry and Molecular Cell Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,ChinaDepartment of Biochemistry and Molecular Cell Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China
医药卫生
AML branched-chainamino acidsLeukemogenesisOxidative stressPI3K/AKT/mTORsignalingUCP2
《Genes & Diseases》 2026 (4)
P.521-537,17
supported by the Natural Science Foundation of Shanghai,China(No.23ZR1436100)the National Key R&D Program of China(No.2020TFA0803603)the National Natural Science Foundation of China(No.82370186,82030075,82230049).
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