title: 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.
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Konno
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka 565-0871, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Asai
authors.affiliation: Department of Gastroenterological Surgery Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Department of Gastroenterological Surgery Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka 565-0871, Japan.
authors.forename: Taroh
authors.initials: T
authors.lastname: Satoh
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka 565-0871, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka 565-0871, Japan.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
mesh_terms: D000619:Aminohydrolases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005472:Fluorouracil / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D012696:Glycine Hydroxymethyltransferase / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D055442:Metabolome; D008715:Methionine / Q000378:metabolism*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D058990:Molecular Targeted Therapy / Q000379:methods*; D009097:Multienzyme Complexes / Q000378:metabolism; D009705:Nucleosides / Q000627:therapeutic use; D009711:Nucleotides / Q000627:therapeutic use; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D000099295:Formyltetrahydrofolate Dehydrogenase
chemical_list: D000619:Aminohydrolases; D000970:Antineoplastic Agents; D005472:Fluorouracil; D005492:Folic Acid; D005493:Folic Acid Antagonists; D012696:Glycine Hydroxymethyltransferase; D008715:Methionine; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D035683:MicroRNAs; D009097:Multienzyme Complexes; D009705:Nucleosides; D009711:Nucleotides; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011687:Purines; D017382:Reactive Oxygen Species; D012694:Serine; D000099295:Formyltetrahydrofolate Dehydrogenase; C055342:methylene tetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase; C520541:SHMT protein, human; C030985:purine