TY - JOUR
T1 - Hypoxia-inducible factors enhance glutamate signaling in cancer cells
AU - Hu, Hongxia
AU - Takano, Naoharu
AU - Xiang, Lisha
AU - Gilkes, Daniele M.
AU - Luo, Weibo
AU - Semenza, Gregg L.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - AMPA receptor
KW - Clear cell renal carcinoma
KW - HIF-1
KW - Hepatocellular carcinoma
UR - http://www.scopus.com/inward/record.url?scp=84910077247&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84910077247&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.2593
DO - 10.18632/oncotarget.2593
M3 - Article
C2 - 25326682
AN - SCOPUS:84910077247
SN - 1949-2553
VL - 5
SP - 8853
EP - 8868
JO - Oncotarget
JF - Oncotarget
IS - 19
ER -