The one-carbon metabolism pathway highlights therapeutic targets for gastrointestinal cancer (Review)

Abstract

After the initial use of anti-folates for treatment of malignancies, folate metabolism has emerged as a rational diagnostic and therapeutic target in gastrointestinal cancer. The one-carbon metabolic pathway, which comprises three critical reactions (i.e., folate and methionine cycles), underlies this effect in conjunction with the trans-sulfuration pathway. Understanding of the one-carbon metabolism pathway has served to unravel the link between the causes and effects of cancer phenotypes leading to several seminal discoveries such as that of diadenosine tri-phosphate hydrolase, microRNAs, 5-FU and, more recently, trifluridine. In the folate cycle, glycine and serine fuel the mitochondrial enzymes SHMT2, MTHFD2 and ALDH1L2, which play critical roles in the cancer survival and proliferation presumably through purine production. In the methionine cycle, S-adenocyl methionine serves hydrocarbons and polyamines that are critical for the epigenetic controls. The trans-sulfuration pathway is a critical component in the synthesis of glutathione, which is involved in the production of reactive oxygen species in cancer stem cells. Therefore, characterization of one-carbon metabolism is indispensable to the development of precision medicine in the context of cancer diagnostics and therapeutics. In the present study, we review the historical issues associated with one-carbon metabolism and highlight the recent advances in cancer research.

Comparison of ESI‐MS/MS and APCI‐MS methods for the quantification of folic acid analogs in C. elegans

“…Folates play a major role in several physiological processes and biological reactions including methylation, DNA biosynthesis and amino acids, and purine and pyrimidine synthesis. Tetrahydrofolate, the active form of this vitamin, acts as one‐carbon donor in S‐adenosylmethionine and S‐adenosylhomocysteine‐dependent methylation reactions, creatine metabolism, and phosphatidylethanolamine methylation . The folate cycle is not only essential to organismal metabolism but is also of medical relevance.…”

Methionine is required for cAMP‐PKA‐mediated morphogenesis and virulence of Candida albicans

“…This antioxidant consists of three amino acids, such as glutamate, cysteine and glycine, and in C. albicans, an enzyme in its synthesis, gamma-glutamylcysteinesynthase, has been shown to be essential for survival in human macrophages in vitro as well as for virulence in a mouse model for disseminated infection (Yadav et al, 2011). Furthermore, glutathione synthesis in cancer stem cells is important as well (Konno et al, 2017).…”

Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy

“…This mitochondrial thiol antioxidant system supports and provides electron sources for both the thioredoxin and glutaredoxin systems via NADPH, which is a major product of nicotinamide nucleotide transhydrogenase, glucose 6-phosphate dehydrogenase, and IDH2 (86). Folate metabolism is also strongly linked to thiol metabolism through the regulation of NADPH, formate, purine biosynthesis, and GSH metabolism (87)(88)(89)(90)(91), providing many new points of cancer cell-specific therapeutic intervention.…”