title: Hypoxia-inducible factors enhance glutamate signaling in cancer cells.
abstract: Signaling through glutamate receptors has been reported in human cancers, but the molecular mechanisms are not fully delineated. We report that in hepatocellular carcinoma and clear cell renal carcinoma cells, increased activity of hypoxia-inducible factors (HIFs) due to hypoxia or VHL loss-of-function, respectively, augmented release of glutamate, which was mediated by HIF-dependent expression of the SLC1A1 and SLC1A3 genes encoding glutamate transporters. In addition, HIFs coordinately regulated expression of the GRIA2 and GRIA3 genes, which encode glutamate receptors. Binding of glutamate to its receptors activated SRC family kinases and downstream pathways, which stimulated cancer cell proliferation, apoptosis resistance, migration and invasion in different cancer cell lines. Thus, coordinate regulation of glutamate transporters and receptors by HIFs was sufficient to activate key signal transduction pathways that promote cancer progression.
authors.affiliation: Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Hu
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Naoharu
authors.initials: N
authors.lastname: Takano
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Lisha
authors.initials: L
authors.lastname: Xiang
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Daniele M
authors.initials: DM
authors.lastname: Gilkes
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D027341:Excitatory Amino Acid Transporter 1 / Q000096:biosynthesis; D050580:Excitatory Amino Acid Transporter 3 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D018698:Glutamic Acid / Q000378:metabolism; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007680:Kidney Neoplasms / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D051076:Proto-Oncogene Proteins c-fyn / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D018091:Receptors, AMPA / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D027341:Excitatory Amino Acid Transporter 1; D050580:Excitatory Amino Acid Transporter 3; D018698:Glutamic Acid; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051076:Proto-Oncogene Proteins c-fyn; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human; C497442:HIF1A protein, human; C493400:SLC1A1 protein, human; C493394:SLC1A3 protein, human; C104723:glutamate receptor ionotropic, AMPA 3; C494957:FYN protein, human; C104722:glutamate receptor ionotropic, AMPA 2