IRE1 Signaling Is Essential for Ischemia-Induced Vascular Endothelial Growth Factor-A Expression and Contributes to Angiogenesis and Tumor Growth In vivo
Open Access
- 15 July 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (14), 6700-6707
- https://doi.org/10.1158/0008-5472.can-06-3235
Abstract
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 Ire1α-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. [Cancer Res 2007;67(14):6700–7]Keywords
Other Versions
This publication has 45 references indexed in Scilit:
- Acute L‐glutamine deprivation compromises VEGF‐a upregulation in A549/8 human carcinoma cellsJournal of Cellular Physiology, 2007
- Novel Therapeutic Targets: The PERKs of Inhibiting the Integrated Stress ResponseCell Cycle, 2006
- Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein ResponseScience, 2006
- Genetic Interactions Due to Constitutive and Inducible Gene Regulation Mediated by the Unfolded Protein Response in C. elegansPLoS Genetics, 2005
- ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growthThe EMBO Journal, 2005
- Glucose Deprivation Increases mRNA Stability of Vascular Endothelial Growth Factor through Activation of AMP-activated Protein Kinase in DU145 Prostate CarcinomaPublished by Elsevier BV ,2005
- Targeting HIF-1 for cancer therapyNature Reviews Cancer, 2003
- The biology of VEGF and its receptorsNature Medicine, 2003
- XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription FactorCell, 2001
- Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1αGenes & Development, 1998