title: Serine catabolism regulates mitochondrial redox control during hypoxia.
abstract: The de novo synthesis of the nonessential amino acid serine is often upregulated in cancer. In this study, we demonstrate that the serine catabolic enzyme, mitochondrial serine hydroxymethyltransferase (SHMT2), is induced when MYC-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO2 and NH4+, resulting in net production of NADPH from NADP+. Knockdown of SHMT2 in MYC-dependent cells reduced cellular NADPH:NADP+ ratio, increased cellular reactive oxygen species, and triggered hypoxia-induced cell death. In vivo, SHMT2 suppression led to impaired tumor growth. In MYC-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and hypoxia-inducible factor-1 α (HIF1α), and SHMT2 expression correlated with unfavorable patient prognosis. Together, these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival.
  
  
  CONCLUSIONS
  In this study, we demonstrate that the mitochondrial enzyme SHMT2 is induced upon hypoxic stress and is critical for maintaining NADPH production and redox balance to support tumor cell survival and growth.
authors.affiliation: Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jiangbin
authors.initials: J
authors.lastname: Ye
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, New Jersey.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.
authors.forename: Ying-Wooi
authors.initials: YW
authors.lastname: Wan
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pawel
authors.affiliation: Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lydia W S
authors.initials: LW
authors.lastname: Finley
authors.affiliation: Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.affiliation: Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Tullia
authors.initials: T
authors.lastname: Lindsten
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: Provincial Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Qing
authors.affiliation: Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, Texas.
authors.forename: Zhandong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine and Howard Hughes Medical Institute, Philadelphia, Pennsylvania.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.affiliation: Lewis-Sigler Institute for Integrative Genomics and Department of Chemistry, Princeton University, Princeton, New Jersey.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: Cancer Biology and Genetics Program and Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York. thompsonc@mskcc.org.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D005784:Gene Amplification; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D016259:Genes, myc; D012696:Glycine Hydroxymethyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006706:Homeostasis; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D047368:Tumor Burden / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human