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.

No abstract

It is well established that thiamine deficiency results in an excess of metabolic intermediates such as lactate and pyruvate, which is likely due to insufficient levels of cofactor for the function of thiamine-dependent enzymes. When in excess, both pyruvate and lactate can increase the stabilization of the hypoxia-inducible factor 1-alpha (HIF-1α) transcription factor, resulting in the trans-activation of HIF-1α regulated genes independent of low oxygen, termed pseudo-hypoxia. Therefore, the resulting dysfunction in cellular metabolism and accumulation of pyruvate and lactate during thiamine deficiency may facilitate a pseudo-hypoxic state. In order to investigate the possibility of a transcriptional relationship between hypoxia and thiamine deficiency, we measured alterations in metabolic intermediates, HIF-1α stabilization, and gene expression. We found an increase in intracellular pyruvate and extracellular lactate levels after thiamine deficiency exposure to the neuroblastoma cell line SK-N-BE. Similar to cells exposed to hypoxia, there was a corresponding increase in HIF-1α stabilization and activation of target gene expression during thiamine deficiency, including glucose transporter-1 (GLUT1), vascular endothelial growth factor (VEGF), and aldolase A. Both hypoxia and thiamine deficiency exposure resulted in an increase in the expression of the thiamine transporter SLC19A3. These results indicate thiamine deficiency induces HIF-1α-mediated gene expression similar to that observed in hypoxic stress, and may provide evidence for a central transcriptional response associated with the clinical manifestations of thiamine deficiency.

No abstract

Ensuring continuous intracellular supply of thiamine is essential to maintain metabolism. Cellular homeostasis requires the function of the membrane bound thiamine transporters THTR1 and THTR2. In the absence of increased dietary intake of thiamine, varying intracellular levels to meet metabolic demands during pathophysiological stressors, such as hypoxia, requires adaptive regulatory mechanisms to increase thiamine transport capacity. Previous work has established the up-regulation of SLC19A3 (THTR2) gene expression and activity during hypoxic stress through the activity of the hypoxia inducible transcription factor 1 alpha (HIF-1α). However, it is unknown whether HIF-1α acts directly or indirectly to trans-activate expression of SLC19A3. This work utilized the breast cancer cell line BT-474 treated with 1% O2 or a hypoxia chemical mimetic deferoxamine to determine the minimal promoter region of SLC19A3 responsible for hypoxia responsiveness. In silico sequence analysis determined two contiguous hypoxia responsive elements in close proximity to the transcriptional start site of the SLC19A3 gene. Using a HIF-1α transcriptional factor ELISA assay, HIF-1α was capable of binding to a dsDNA construct of the SLC19A3 minimal promoter. Chromatin immunoprecipitation assay established that SP1 was bound to the SLC19A3 minimal promoter region under normoxic conditions. However, HIF-1α binding to the minimal promoter region occurred during hypoxic treatments, while no SP1 binding was observed under these conditions. This work demonstrates the direct binding and activation of SLC19A3 expression by HIF-1α during hypoxic stress, suggesting an important adaptive regulatory role for HIF-1α in maintaining thiamine homeostasis.