Downregulation of PCK2 remodels tricarboxylic acid cycle in tumor-repopulating cells of melanoma.
For cancer cells to proliferate, a balance must be built between biomass-forming, glucose-metabolized intermediates and ATP production. How intrinsic glucose carbon flow regulates this balance remains unclear. Here we show that mitochondrial phosphoenolpyruvate carboxykinase (PCK2), the hub molecule linking tricarboxylic acid (TCA) cycle, glycolysis and gluconeogenesis by conversion of mitochondrial oxaloacetate (OAA) to phosphoenolpyruvate, regulates glucose carbon flow direction in stem-like cells that repopulate tumors (tumor-repopulating cells (TRCs)). PCK2 downregulation accelerated biosynthesis and transportation of citrate from mitochondria to the cytosol, leading to cytosolic glucose carbon flow via OAA-malate-pyruvate and acetyl-CoA-fatty acid pathways in TRCs. On the other hand, downregulating PCK2 hindered fumarate carbon flows in TCA cycle, leading to attenuated oxidative phosphorylation. In pathological terms, PCK2 overexpression slowed TRC growth in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled unexpected glucose carbon flows of TRCs in melanoma that have implications for targeting metabolic aspects of melanoma.
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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Luo
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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Y
Li
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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R
Ma
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
J
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Liu
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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Xu
State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Zhang
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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Tang
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
J
J
Ma
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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Liu
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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Y
Zhang
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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Y
Sun
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.
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T
Ji
State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Liang
State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Yin
State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Y
Liu
Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Tong
Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Niu
Laboratory for Cell Biomechanics and Regenerative Medicine, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.|Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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N
Wang
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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X
Wang
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science andTechnology, Wuhan, China.|State Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
B
B
Huang
D000818:Animals; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010085:Oxidative Phosphorylation; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis* / Q000235:genetics
D009363:Neoplasm Proteins; C000597251:PCK2 protein, human; D019764:Phosphoenolpyruvate Carboxykinase (ATP)