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.
Highlights
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
Transport of TPP across the mitochondrial membrane to support pyruvate dehydrogenase (PDH) and Alpha-ketoglutarate dehydrogenase (α-KGDH) activity is facilitated by the thiamine pyrophosphate carrier (TPC), which is encoded by the SLC25A19 gene [18]
The alterations in thiamine homeostasis and increase in cancer cell proliferation with thiamine supplementation highlights a significant role for thiamine in cancer
Summary
Shown to transport reduced folate or other organic cations [4,5]. SLC19A2 and SLC19A3 transport thiamine with Km values of 2.5 μM and 27 nM, respectively [6,7]. Increased oxidative stress in cancer cells was demonstrated to suppress M2-PK activity and enhance flux through the oxidative PPP with a concomitant decrease in reduced glutathione levels [95]. When exposed to hypoxic stress, reducing TKTL1 expression has resulted in an increase in ROS generation and cell death to glioma cells [96] It is unclear how TKTL1 activity in the non-oxidative PPP is related to NADPH production generated within the oxidative pathway. Increasing concentrations of TPP through thiamine supplementation may be proapoptotic through restoration of PDH activity in cancer cells This may explain why a reduction in tumor growth was observed with high-dose thiamine supplementation [58]. Further research is required to establish if any relationship between thiamine supplementation with BCAA metabolism and cancer cachexia exists
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