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

Abstract

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 ...

Hypoxia induced upregulation and function of the thiamine transporter, SLC19A3 in a breast cancer cell line

“…44 TKTL1 activity has been shown to supply ~85% of the C5-ribose sugars for nucleic acid synthesis, be overexpressed in a range of cancers including breast, and be essential for tumor cell proliferation. [45][46][47][48][49][50] Our results not only demonstrated an increase in SLC19A3 transporter expression but an increase in overall thiamine transport which could potentially be supporting the glycolytic phenotype of hypoxic cancer cells (Fig. 3).…”

Tumor cell metabolism

“…TKTL1 inhibition also diminishes cell proliferation in several types of cancer cells, 103 indicating its importance in tumor cell proliferation.…”

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

“…Human colon carcinoma cells with suppressed TKTL1 activity display reduced cell proliferation, lactate production, glutathione content, and NADPH/NADP þ ratio, as well as an increase in ROS-induced apoptosis. Lower amounts of these antioxidants may alter the ability of cells to detoxify ROS (86). The cellular redox status can also be modulated by directly targeting glutathione.…”