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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Renal Cell / genetics*
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Cell Hypoxia
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Cell Line, Tumor
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Cell Proliferation / genetics
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Excitatory Amino Acid Transporter 1 / biosynthesis
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Excitatory Amino Acid Transporter 3 / biosynthesis
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Gene Expression Regulation, Neoplastic
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Glutamic Acid / metabolism
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HEK293 Cells
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Heterografts
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
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Kidney Neoplasms / genetics
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Liver Neoplasms / genetics*
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Male
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Mice
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Mice, SCID
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Neoplasm Transplantation
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Proto-Oncogene Proteins c-fyn / biosynthesis
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RNA Interference
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RNA, Small Interfering
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Receptors, AMPA / biosynthesis
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Signal Transduction / genetics
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Von Hippel-Lindau Tumor Suppressor Protein / genetics
Substances
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ARNT protein, human
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Basic Helix-Loop-Helix Transcription Factors
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Excitatory Amino Acid Transporter 1
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Excitatory Amino Acid Transporter 3
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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RNA, Small Interfering
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Receptors, AMPA
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SLC1A1 protein, human
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SLC1A3 protein, human
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glutamate receptor ionotropic, AMPA 3
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Aryl Hydrocarbon Receptor Nuclear Translocator
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endothelial PAS domain-containing protein 1
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Glutamic Acid
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Von Hippel-Lindau Tumor Suppressor Protein
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FYN protein, human
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Proto-Oncogene Proteins c-fyn
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glutamate receptor ionotropic, AMPA 2