IRE1 Signaling Is Essential for Ischemia-Induced Vascular Endothelial Growth Factor-A Expression and Contributes to Angiogenesis and Tumor Growth In vivo

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

Inhibition of IRE1 modifies hypoxic regulation of G6PD, GPI, TKT, TALDO1, PGLS and RPIA genes expression in U87 glioma cells

“…In this study we used sublines of U87 glioma cells, which were described previously [5,9]. One subline was obtained by selection of stable transfec ted clones with overexpression of vector pcDNA3.1, which was used for creation of dnIRE1 (dominant/ negative IRE1).…”

“…Investi gation of the expression of G6PD, tkt, TALDO1, PGLS, rPIA, and GPI genes in glioma cells upon hypoxia in respect to inhibition of IRE1 signaling is important for understanding the malignant tumor growth mechanisms, because hypoxia as well as endoplasmic reticulum stress play an essential role in the control of tumor progression [10,32,34,38,39]. The growing tumor requires the endoplasmic reticulum stress and hypoxia for apoptosis inhibi tion, neovascularization and growth [5,38,40]. Cell proliferation is strongly dependent on hypoxia and glycolysis because there is the molecular connection between cell cycle progression and the provision of substrates essential for this purpose [6,39,40].…”

Stress du réticulum endoplasmique

“…En effet des études ont montré que l'inhibition de la signalisation de la protéine IRE1 induisait une diminution de la croissance et de l'angiogenèse tumorales. IRE1 permettrait l'adaptation des cellules tumorales à leur environnement ischémique en induisant entre autres la production de facteurs pro-angiogéniques tel que le VEGF-A (vascular endothelial growth factor) [37]. Il en est de même pour XBP1, qui est également impliqué dans le développement tumoral [38,39].…”

Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition

“…However, involving of endoplasmic reticulum (ER) stress signaling into the regulation of diff erent metabolic processes by estrogens has not been explored yet. Th e ER stress is mediated by three sensor and signaling pathways, but inositol requiring enzyme 1 (IRE1/ERN1) is a central mediator of the unfolded protein response and an important component of tumor growth, because its inhibition leads to a suppression of glioma growth through down-regulation of the angiogenesis and proliferation processes (Drogat et al 2007;Auf et al 2010Auf et al , 2013. Th is stress is recognized as an important determinant of cancer and contributes to the expression profi le of many regulatory genes resulting in proliferation, apoptosis, angiogenesis, and circadian clock (Clarke et al 2014;Manie et al 2014;Pluquet et al 2014;Dejeans et al 2015;Minchenko et al 2015).…”