Iron promotes glycolysis to drive colon tumorigenesis.

Autor: Liu Z; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA., Villareal L; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA., Goodla L; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA., Kim H; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA., Falcon DM; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA., Haneef M; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA., Martin DR; Department of Pathology, University of New Mexico, Albuquerque, NM 87131, USA., Zhang L; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA., Lee HJ; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA., Kremer D; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA., Lyssiotis CA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA., Shah YM; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA., Lin HC; Section of Gastroenterology, Medicine Service, New Mexico VA Health Care System, Albuquerque, NM 87108, USA; Division of Gastroenterology and Hepatology, Department of Medicine, the University of New Mexico, Albuquerque, NM, 87131, USA., Lin HK; Department of Pathology, Duke University, Durham, NC 27710, USA., Xue X; Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM 87131, USA. Electronic address: xxue@salud.unm.edu.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2023 Dec; Vol. 1869 (8), pp. 166846. Date of Electronic Publication: 2023 Aug 12.
DOI: 10.1016/j.bbadis.2023.166846
Abstrakt: Colorectal cancer (CRC) is the third most common cancer and is also the third leading cause of cancer-related death in the USA. Understanding the mechanisms of growth and progression of CRC is essential to improve treatment. Macronutrients such as glucose are energy source for a cell. Many tumor cells exhibit increased aerobic glycolysis. Increased tissue micronutrient iron levels in both mice and humans are also associated with increased colon tumorigenesis. However, if iron drives colon carcinogenesis via affecting glucose metabolism is still not clear. Here we found the intracellular glucose levels in tumor colonoids were significantly increased after iron treatment. 13 C-labeled glucose flux analysis indicated that the levels of several labeled glycolytic products were significantly increased, whereas several tricarboxylic acid cycle intermediates were significantly decreased in colonoids after iron treatment. Mechanistic studies showed that iron upregulated the expression of glucose transporter 1 (GLUT1) and mediated an inhibition of the pyruvate dehydrogenase (PDH) complex function via directly binding with tankyrase and/or pyruvate dehydrogenase kinase (PDHK) 3. Pharmacological inhibition of GLUT1 or PDHK reactivated PDH complex function and reduced high iron diet-enhanced tumor formation. In conclusion, excess iron promotes glycolysis and colon tumor growth at least partly through the inhibition of the PDH complex function.
Competing Interests: Declaration of competing interest C.A.L. has received consulting fees from Astellas Pharmaceuticals and Odyssey Therapeutics and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015).
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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