title: Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma.
abstract: Cancer cells preferentially utilize glucose and glutamine, which provide macromolecules and antioxidants that sustain rapid cell division. Metabolic reprogramming in cancer drives an increased glycolytic rate that supports maximal production of these nutrients. The folate cycle, through transfer of a carbon unit between tetrahydrofolate and its derivatives in the cytoplasmic and mitochondrial compartments, produces other metabolites that are essential for cell growth, including nucleotides, methionine, and the antioxidant NADPH. Here, using hepatocellular carcinoma (HCC) as a cancer model, we have observed a reduction in growth rate upon withdrawal of folate. We found that an enzyme in the folate cycle, methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L), plays an essential role in support of cancer growth. We determined that MTHFD1L is transcriptionally activated by NRF2, a master regulator of redox homeostasis. Our observations further suggest that MTHFD1L contributes to the production and accumulation of NADPH to levels that are sufficient to combat oxidative stress in cancer cells. The elevation of oxidative stress through MTHFD1L knockdown or the use of methotrexate, an antifolate drug, sensitizes cancer cells to sorafenib, a targeted therapy for HCC. Taken together, our study identifies MTHFD1L in the folate cycle as an important metabolic pathway in cancer cells with the potential for therapeutic targeting.
authors.forename: Derek
authors.initials: D
authors.lastname: Lee
authors.forename: Iris Ming-Jing
authors.initials: IM
authors.lastname: Xu
authors.forename: David Kung-Chun
authors.initials: DK
authors.lastname: Chiu
authors.forename: Robin Kit-Ho
authors.initials: RK
authors.lastname: Lai
authors.forename: Aki Pui-Wah
authors.initials: AP
authors.lastname: Tse
authors.forename: Lynna
authors.initials: L
authors.lastname: Lan Li
authors.forename: Cheuk-Ting
authors.initials: CT
authors.lastname: Law
authors.forename: Felice Ho-Ching
authors.initials: FH
authors.lastname: Tsang
authors.forename: Larry Lai
authors.initials: LL
authors.lastname: Wei
authors.forename: Cerise Yuen-Ki
authors.initials: CY
authors.lastname: Chan
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
mesh_terms: D000619:Aminohydrolases / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism*; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009097:Multienzyme Complexes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase