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Suppression of UCP2 alleviates leukemogenesis by enhancing branched amino acids induced oxidative stress via activating PI3K/AKT/mTOR signaling

ABSTRACT: Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis have been reported in various solid tumor models, its role in leukemogenesis remain elusive. Here, we demonstrated that UCP2 was highly expressed in AML, and it is significantly associated with chemoresistance and poor prognosis suggesting that UCP2 can be a potential biomarker for AML treatment. Mechanically, in vitro and in vivo silencing of UCP2 significantly impairs AML cell growth, survival and accompanied with the disruption of mitochondria homeostasis. Interestingly, RNA-seq analysis and metabolic mass spectrometry revealed that silencing UCP2 results in accumulation of branched chain amino acids (BCAA), which in turn induced oxidative stress through activating PI3K/AKT and mTOR signaling pathway. Additionally, lack of BCAA restored leukemic cell growth, cell survival and decreased mitochondria ROS production which is induced by inhibiting UCP2. Notably, supplementation of BCAA enhanced anti-tumor activity of Genipin, a selective inhibitor that targets UCP2, results in significant reduction of AML blasts, increased mice survival and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provide a novel strategy for leveraging the metabolic dependencies of leukemic cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284102 | GEO | 2026/04/22

REPOSITORIES: GEO

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Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H). This model is described in the article: Computational Modelling of the Metabolic States Regulated by the Kinase Akt. Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L. Frontiers in Systems Biology. 2012 Oct 13 Abstract: Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism. This model is hosted on BioModels Database and identified by: MODEL1210150000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Suppression of UCP2 alleviates leukemogenesis by enhancing branched amino acids induced oxidative stress via activating PI3K/AKT/mTOR signaling

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