IRE1 signaling is essential for ischemia-induced vascular endothelial growth factor-A expression and contributes to angiogenesis and tumor growth in vivo.
In solid tumors, cancer cells subjected to ischemic conditions trigger distinct signaling pathways contributing to angiogenic stimulation and tumor development. Characteristic features of tumor ischemia include hypoxia and glucose deprivation, leading to the activation of hypoxia-inducible factor-1-dependent signaling pathways and to complex signaling events known as the unfolded protein response. Here, we show that the activation of the endoplasmic reticulum stress sensor IRE1 is a common determinant linking hypoxia- and hypoglycemia-dependent responses to the up-regulation of vascular endothelial growth factor-A (VEGF-A). Tumor cells expressing a dominant-negative IRE1 transgene as well as Ire1alpha-null mouse embryonic fibroblasts were unable to trigger VEGF-A up-regulation upon either oxygen or glucose deprivation. These data correlated with a reduction of tumor angiogenesis and growth in vivo. Our results therefore suggest an essential role for IRE1-dependent signaling pathways in response to ischemia and identify this protein as a potential therapeutic target to control both the angiogenic switch and tumor development.
Drogat
Benjamin
B
INSERM E0113, Université Bordeaux I, Bâtiment B2, Avenue des Facultes, Falence F-33400, France.
Auguste
Patrick
P
Nguyen
Duc Thang
DT
Bouchecareilh
Marion
M
Pineau
Raphael
R
Nalbantoglu
Josephine
J
Kaufman
Randal J
RJ
Chevet
Eric
E
Bikfalvi
Andréas
A
Moenner
Michel
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004722:Endoribonucleases / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006801:Humans; D007511:Ischemia; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D010100:Oxygen