title: Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype.
abstract: Reduced oxygen availability (hypoxia) leads to increased production of reactive oxygen species (ROS) by the electron transport chain. Here, I review recent work delineating mechanisms by which hypoxia-inducible factor 1 (HIF-1) mediates adaptive metabolic responses to hypoxia, including increased flux through the glycolytic pathway and decreased flux through the tricarboxylic acid cycle, in order to decrease mitochondrial ROS production. HIF-1 also mediates increased flux through the serine synthesis pathway and mitochondrial one-carbon (folate cycle) metabolism to increase mitochondrial antioxidant production (NADPH and glutathione). Dynamic maintenance of ROS homeostasis is required for induction of the breast cancer stem cell phenotype in response to hypoxia or cytotoxic chemotherapy. Consistently, inhibition of phosphoglycerate dehydrogenase, the first enzyme of the serine synthesis pathway, in breast cancer cells impairs tumor initiation, metastasis, and response to cytotoxic chemotherapy. I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer.
authors.affiliation: Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, McKusick-Nathans Institute of Genetic Medicine, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA gsemenza@jhmi.edu.
authors.forename: Gregg L
authors.identifier: 0000-0002-0913-211X
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000201:enzymology / Q000502:physiology*
chemical_list: D000975:Antioxidants; D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D005947:Glucose
keywords: cancer; one‐carbon metabolism; pluripotency; progression; serine synthesis