A comparison of C14-labeling patterns in deoxyribose and ribose in mammalian cells

Horecker, B.L.; Domagk, Götz F.; Hiatt, Howard H.

doi:10.1016/0003-9861(58)90375-8

Cited by 36 publications

(13 citation statements)

References 22 publications

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“…We show that both, a lower glucose consumption and L-lactic acid production rate are induced by TKTL1 suppression as anticipated from the assumed role of TKTL1 as major regulator of PPP in tumor cells 30 although we can not formally exclude the possibility that these metabolic changes are only indirectly affected by TKTL1 suppression. In line with direct effects of TKTL1 on glucose metabolism (and lactate production), recent studies utilizing radioactively labeled glucose have revealed that glucose, besides its central role in energy production, is the main source of tumor cell RNA and DNA pentoses 37,38 and de novo lipid synthesis. 39 The strong proliferation process of tumor cells is governed by the replication of DNA in the S phase where the conversion of glucose to ribose is controlled by nonoxidative PPP.…”

Section: Discussionmentioning

confidence: 96%

Transketolase‐like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

Hausen

Coy³

et al. 2008

Intl Journal of Cancer

126

124

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Cancer cells display high rates of aerobic glycolysis, a phenomenon known as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are overproduced by cancer cells even in the presence of oxygen. The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis, glucose degradation to lactate, and regeneration of redox equivalents. The nonoxidative part of the PPP is controlled by transketolase (TKT) enzymes. One TKT isoform, the transketolase-like protein 1 (TKTL1) is specifically upregulated in different human cancers and its overexpression predicts a poor patient's survival. This finding implicates that an increased TKTL1 expression may activate the PPP leading to enhanced cancer cell growth and survival. To analyze the functional role of TKTL1 in malignant progression, we inhibited TKTL1 by RNAi technologies in human HCT116 colon carcinoma cells. TKTL1 suppression resulted in a significantly slowed cell growth, glucose consumption and lactate production. In TKTL1 knockdown-cells, the intracellular reactive oxygen species levels were not significantly increased, whereas the sensitivity towards oxidative stress-induced apoptosis was clearly enhanced. These data provide new clues on the importance of TKTL1 dys-regulation in tumor cells and indicate that TKTL1 overexpression may be considered not only as a new tumor marker but also as a good target for anticancer therapy. ' 2008 Wiley-Liss, Inc.Key words: TKTL1; aerobic glycolysis; shRNA; reactive oxygen species (ROS) Cancer is caused by endogenous and exogenous factors leading to the sequential accumulation of genetic alterations, a scenario known as multistep oncogenesis.1 Organotypically different tumors are often characterized by related or even identical changes in cell physiology and cell metabolism.2 A characteristic of solid, malignant tumors is the strongly enhanced glycolytic metabolism of carbohydrates even in the presence of oxygen, the so-called aerobic glycolysis or Warburg effect.3 This feature characterizes cancer metabolism as highly inefficient by breaking down excess amounts of glucose to lactate even in the presence of oxygen.3 Despite the controversy on the relation between aerobic glycolysis and cancer biology 4,5 the widespread clinical use of positron-emission tomography (PET) for the detection of aerobic glycolysis in tumors and recent findings have rekindled interest in physiological changes during malignant conversion and metabolic signatures for different stages of tumorigenesis. Although an increase in glucose uptake and lactate production have been correlated to tumor progression, the fully transformed state is most dependent on aerobic glycolysis and almost not on the mitochondrial machinery for ATP synthesis. Thus, aerobic glycolysis can be conceived as a form of tumor adaptation for conditions of reduced or inefficient oxygen supply.Although the biochemical and molecular mechanisms leading to increased aerobic glycolysis in tumors are complex and may be attributed to multiple ...

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Section: Discussionmentioning

confidence: 96%

Transketolase‐like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

Hausen

Coy³

et al. 2008

Intl Journal of Cancer

126

124

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“…Studies utilizing isotopically labeled glucose carbons recovered from in vivo hosted Yoshida tumors or in vitro cultured HeLa, Mia, H9, and Hep G2 cells unequivocally demonstrated that the nonoxidative part of the pentose cycle plays a significant role in tumor cell nucleic acid synthesis (1)(2)(3)(4). More than 70% of nucleic acid ribose in these tumor cells was derived through transketolase, transaldolase, and triose phosphate isomerase reactions and only 10-15% was derived directly through the oxidative steps.…”

Section: Tumor Cell Nucleic Acid Ribose Synthesis Pathways-data Behinmentioning

confidence: 99%

“…Tumor cells have been shown to heavily utilize the nonoxidative transketolase pathway for ribose synthesis to build nucleic acid, in addition to the oxidative glucose-6-phosphate dehydrogenase (G-6-PD) pathway, the main ribose-producing reaction in the classical model of the pentose cycle (1)(2)(3)(4). Metabolic substrate flux control coefficients of enzymes can be used to identify target sites that have maximal influence on the metabolic pathway flux, thereby assisting in the development of drugs that will have the highest possible efficacy (5).…”

Section: Introductionmentioning

confidence: 99%

Role of Thiamin (Vitamin B-1) and Transketolase in Tumor Cell Proliferation

Cascante¹,

Centelles²,

Veech³

et al. 2000

Nutrition and Cancer

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Metabolic control analysis predicts that stimulators of transketolase enzyme synthesis such as thiamin (vitamin B-1) support a high rate of nucleic acid ribose synthesis necessary for tumor cell survival, chemotherapy resistance, and proliferation. Metabolic control analysis also predicts that transketolase inhibitor drugs will have the opposite effect on tumor cells. This may have important implications in the nutrition and future treatment of patients with cancer.

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“…Studies utilizing isotopically labelled glucose carbons recovered from tumor cell RNA and DNA have revealed that glucose carbons are also the main source of de novo lipid [5] and nucleic acid synthesis [6,7] besides their central role in energy production. Therefore, glucose utilizing intracellular anabolic pathways in the PC offers a new approach to tumor therapy [8].…”

Section: Introductionmentioning

confidence: 99%

Oxythiamine and dehydroepiandrosterone induce a G₁ phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle

et al. 1999

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Transketolase (TK) reactions play a crucial role in tumor cell nucleic acid ribose synthesis utilizing glucose carbons, yet, current cancer treatments do not target this central pathway. Experimentally, a dramatic decrease in tumor cell proliferation after the administration of the TK inhibitor oxythiamine (OT) was observed in several in vitro and in vivo tumor models. Here, we demonstrate that pentose cycle (PC) inhibitors, OT and dehydroepiandrosterone (DHEA), efficiently regulate the cell cycle and tumor proliferation processes. Increasing doses of OT or DHEA were administered by daily intraperitoneal injections to Ehrlich's ascites tumor hosting mice for 4 days. The tumor cell number and their cycle phase distribution profile were determined by DNA flow histograms. Tumors showed a dose dependent increase in their G 0 -G 1 cell populations after both OT and DHEA treatment and a simultaneous decrease in cells advancing to the S and G 2 -M cell cycle phases. This effect of PC inhibitors was significant, OT was more effective than DHEA, both drugs acted synergistically in combination and no signs of direct cell or host toxicity were observed. Direct inhibition of PC reactions causes a G 1 cell cycle arrest similar to that of 2-deoxyglucose treatment. However, no interference with cell energy production and cell toxicity is observed. PC inhibitors, specifically ones targeting TK, introduce a new target site for the development of future cancer therapies to inhibit glucose utilizing pathways selectively for nucleic acid production.z 1999 Federation of European Biochemical Societies.

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A comparison of C14-labeling patterns in deoxyribose and ribose in mammalian cells

Cited by 36 publications

References 22 publications

Transketolase‐like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

Transketolase‐like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

Role of Thiamin (Vitamin B-1) and Transketolase in Tumor Cell Proliferation

Oxythiamine and dehydroepiandrosterone induce a G₁ phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle

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A comparison of C14-labeling patterns in deoxyribose and ribose in mammalian cells

Cited by 36 publications

References 22 publications

Transketolase‐like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

Transketolase‐like protein 1 (TKTL1) is required for rapid cell growth and full viability of human tumor cells

Role of Thiamin (Vitamin B-1) and Transketolase in Tumor Cell Proliferation

Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle

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Oxythiamine and dehydroepiandrosterone induce a G₁ phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle