Hypoxia-inducible factors enhance glutamate signaling in cancer cells

Hongxia Hu, Naoharu Takano, Lisha Xiang, Daniele M. Gilkes, Weibo Luo, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8853-8868
Number of pages16
JournalOncotarget
Volume5
Issue number19
DOIs
StatePublished - 2014

Keywords

  • AMPA receptor
  • Clear cell renal carcinoma
  • HIF-1
  • Hepatocellular carcinoma

ASJC Scopus subject areas

  • Oncology

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