Linking vitamin B1 with cancer cell metabolism

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.

Figure 1

Chemical structures of thiamine (vitamin B1; thiamin) and the active co-enzyme thiamine pyrophosphate (thiamine diphosphate; TPP).

Figure 2

Intracellular thiamine homeostasis is initially achieved through the uptake of thiamine (T) by the thiamine transporters THTR1 and THTR2. Once inside the cell, thiamine is converted to the active co-enzyme, thiamine pyrophosphate (TPP) by thiamine pyrophosphokinase-1 (TPK1). Thiamine can than function as a cofactor for the cytoplasmic TKT. Transport of TPP by the thiamine pyrophosphate carrier (TPC) across the mitochondrial membrane supplies cofactor for activity of pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (α-KGDH). Intracellular TPP can also be converted to thiamine monophosphate (TMP) by thiamine pyrophosphatase (TPPase) and subsequently recycled back to thiamine by thiamine monophosphatase (TMPase). Both TMP and TPP can be effluxed out of the cell through the reduced folate carrier (RFC1).

Figure 3

Under normal cell metabolism G6P entering the oxidative pentose phosphate pathway (PPP) is converted to ribose 5-phosphate (R5P) and xylulose 5-phsophate (X5P). Both can be further metabolized through the non-oxidative pathway to ultimately form fructose 6-phosphate (F6P) and glyceraldehyde 3-phosphate (G3P) that re-enters the glycolytic pathway to continue catabolism for ATP production. In cancer, reduced activity of M2-PK leads to an excess of F6P and G3P that can be shunted back into the non-oxidative pathway for anabolism. Mediated through transaldolase (TA) and the TPP-dependent enzyme TKT, F6P and G3P are converted to R5P for biosynthesis of nucleotides.

Figure 4

The pyruvate dehydrogenase (PDH) complex converts pyruvate into acetyl-CoA when bound to the co-enzyme, thiamine pyrophosphate (TPP). In cancer, phosphorylation of PDH by pyruvate dehydrogenase kinase isoforms 1 to 4 (PDK1 to 4) inactivates PDH, leading to a reduction, in pyruvate conversion to lactate by lactate dehydrogenase A (LDHA). Inhibition of PDK activity by dichloroacetate (DCA) reduces phosphorylation and induces apoptosis. TPP binding to PDH has also been suggested to inhibit PDK phosphorylation and may explain why high dose thiamine has anti-proliferative effects in a tumor xenograft model. In the oxidative direction, pyruvate is converted to acetyl-CoA by PDH and is continually catabolized to α-ketoglutarate. The thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase (α-KGDH) converts α-ketoglutarate to succinyl-CoA. Cancer cells exploit glutaminolysis to resupply the tricarboxylic acid (TCA) cycle with carbon as α-ketoglutarate. Continuation of the TCA cycle results in anabolic activity to provide precursors for nucleotides, amino acids, and lipids for biomass generation.