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Hypoxia‐inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype
Author(s) -
Semenza Gregg L
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695204
Subject(s) - biology , citric acid cycle , cancer cell , reactive oxygen species , mitochondrial ros , mitochondrion , microbiology and biotechnology , cancer research , biochemistry , metabolism , cancer , genetics
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.