HYPOXIA-INDUCIBLE FACTORS ENHANCE GLUTAMATE SIGNALING IN CANCER CELLS
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Hypoxia-inducible factors (HIFs) are transcription factors that are essential in many developmental, physiological and pathophysiological processes. HIFs can be induced in response to reduced oxygen availability (hypoxia) or as a result of oncogene gain-of-function or tumor suppressor gene loss-of-function. Recent studies have shed light on the key roles of HIFs in almost every aspect of cancer biology. On the other hand, the glutamatergic signaling pathway, which was first studied in neuronal excitability in the central nervous system, now has been reported in various human cancers. However, the molecular mechanisms are not fully delineated, leading us to investigate whether HIFs regulate glutamate signaling in cancer. We show that in hepatocellular and renal carcinoma cells, increased activity of HIFs due to hypoxia or VHL loss-of-function, respectively, augments release of glutamate. After examining the expression of genes which are involved in glutamate transport, we delineated that the glutamate transporters SLC1A1 and SLC1A3 were induced in a HIF-dependent manner. In addition, HIFs coordinately regulate expression of the GRIA2 and GRIA3 genes, which encode α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits, and the expression of FYN, which encodes a SRC family kinase. Binding of glutamate to its cognate receptors activates SRC family kinases and downstream pathways, which stimulate cancer cell proliferation, apoptosis resistance, migration and invasion in a cell-type-specific manner. Analyzing gene expression data from 42 clear cell renal cell carcinomas (ccRCCs) in the TCGA database revealed that SLC1A1, SLC1A3, GRIA3 and FYN mRNA levels were each significantly correlated with the expression of known HIF target genes, indicating that the same transcriptional circuits are active in vivo. Indeed, the AMPA receptor antagonist GYKI 52466 inhibits Hep3B xenograft growth. This coordinated transcriptional activation of glutamate transporters and receptors by HIFs enhances the glutamate autocrine/paracrine signaling circuit, and is sufficient to activate key signal transduction pathways that promote cancer progression.