Transforming growth factor beta2 promotes glucose carbon incorporation into nucleic acid ribose through the nonoxidative pentose cycle in lung epithelial carcinoma cells. Cancer Res

Harbor-UCLA Research and Education Institute, University of California at Los Angeles School of Medicine, Torrance 90502, USA.
Cancer Research (Impact Factor: 9.33). 04/2000; 60(5):1183-5.
Source: PubMed


The invasive transformation of A-459 lung epithelial carcinoma cells has been linked to the autocrine regulation of malignant phenotypic changes by transforming growth factor beta (TGF-beta). Here we demonstrate, using stable 13C glucose isotopes, that the transformed phenotype is characterized by decreased CO2 production via direct glucose oxidation but increased nucleic acid ribose synthesis through the nonoxidative reactions of the pentose cycle. Increased nucleic acid synthesis through the nonoxidative pentose cycle imparts the metabolic adaptation of nontransformed cells to the invasive phenotype that potentially explains the fundamental metabolic disturbance in tumor cells: highly increased nucleic acid synthesis despite hypoxia and decreased glucose oxidation.

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Available from: Marta Cascante, Oct 02, 2015
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    • "Stem cells and cancer cells have a high anabolic requirement. In these cells, PPP can be activated by growth signaling pathways such as TGF b (Boros et al. 2000). Since thiamine is a cofactor for transketolase/transaldolase enzyme, thiamine deficiency either because of genetic transport defect as in The Warburg effect 793 thiamine response megaloblastic anemia (TRMA) (Boros et al. 2003) or anti-thiamine treatment with oxythiamine, retards cell growth which can be rescued with thiamine supplementation (Rais et al. 1999; Comin-Anduix et al. 2001). "
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    ABSTRACT: Cancer metabolism is characterized by increased macromolecular syntheses through coordinated increases in energy and substrate metabolism. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Aerobic glycolysis in cancer metabolism is accompanied by increased pentose cycle and anaplerotic activities producing energy and substrates for macromolecular synthesis. How these processes are coordinated is poorly understood. Recent advances have focused on molecular regulation of cancer metabolism by oncogenes and tumor suppressor genes which regulate numerous enzymatic steps of central glucose metabolism. In the past decade, new insights in cancer metabolism have emerged through the application of stable isotopes particularly from 13C carbon tracing. Such studies have provided new evidence for system-wide changes in cancer metabolism in response to chemotherapy. Interestingly, experiments using metabolic inhibitors on individual biochemical pathways all demonstrate similar system-wide effects on cancer metabolism as in targeted therapies. Since biochemical reactions in the Warburg effect place competing demands on available precursors, high energy phosphates and reducing equivalents, the cancer metabolic system must fulfill the condition of balance of flux (homeostasis). In this review, the functions of the pentose cycle and of the tricarboxylic acid (TCA) cycle in cancer metabolism are analyzed from the balance of flux point of view. Anticancer treatments that target molecular signaling pathways or inhibit metabolism alter the invasive or proliferative behavior of the cancer cells by their effects on the balance of flux (homeostasis) of the cancer metabolic phenotype.
    Metabolomics 12/2014; 11(4):1-10. DOI:10.1007/s11306-014-0760-9 · 3.86 Impact Factor
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    • "While normal cells frequently rely on the oxidative branch of PPP for ribose-5-phosphate production; cancer cells use both arms, e.g., oxidative and non-oxidative, of PPP to generate ribose-5-phosphate for nucleic acid synthesis51-53. Furthermore, cancer cells can use ribose-5-phosphate in both de novo and salvage pathways to synthesize nucleotides. These flexible metabolic programs help cancer cells effectively adapt to constantly changing nutritional conditions of tumor microenvironment. "
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    Cancer Biology and Medicine 03/2014; 11(1):1-19. DOI:10.7497/j.issn.2095-3941.2014.01.001
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    • "In contrast, a shift to increased reliance on the non-oxidative PPP for R5P production is found in cancer cells. Boros et al. demonstrated that 98% of the ribose molecules in H441 lung cancer cells were derived through the non-oxidative pathway [67]. Similarly, 85% of the ribose RNA in pancreatic adenocarcinoma cells was from the non-oxidative pathway [62]. "
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    ABSTRACT: The resurgence of interest in cancer metabolism has linked alterations in the regulation and exploitation of metabolic pathways with an anabolic phenotype that increases biomass production for the replication of new daughter cells. To support the increase in the metabolic rate of cancer cells, a coordinated increase in the supply of nutrients, such as glucose and micronutrients functioning as enzyme cofactors is required. The majority of co-enzymes are water-soluble vitamins such as niacin, folic acid, pantothenic acid, pyridoxine, biotin, riboflavin and thiamine (Vitamin B1). Continuous dietary intake of these micronutrients is essential for maintaining normal health. How cancer cells adaptively regulate cellular homeostasis of cofactors and how they can regulate expression and function of metabolic enzymes in cancer is underappreciated. Exploitation of cofactor-dependent metabolic pathways with the advent of anti-folates highlights the potential vulnerabilities and importance of vitamins in cancer biology. Vitamin supplementation products are easily accessible and patients often perceive them as safe and beneficial without full knowledge of their effects. Thus, understanding the significance of enzyme cofactors in cancer cell metabolism will provide for important dietary strategies and new molecular targets to reduce disease progression. Recent studies have demonstrated the significance of thiamine-dependent enzymes in cancer cell metabolism. Therefore, this review discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells.
    07/2013; 1(1). DOI:10.1186/2049-3002-1-16
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