Endoplasmic reticulum stress, its sensor and signalling systems and the role in regulation of gene expression at malignant tumor growth and hypoxia

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

“…It is well known that GPI/AMF has proproliferative properties because it contributes to energy pathways and as cytokine (not enzymatic activity) and its si lencing resulted in mesenchymaltoepithelial transi tion of human cancer cells with reduced malignancy [2426]. Thus, our results are mostly consistent with numerous data [9,10,27,40] that hypoxia associated with malignant progression through the endoplasmic reticulum unfolded protein response, but mecha nisms through which malignant cells cope with po tentially lethal metabolic stress induced by hypoxia remains poorly understood. At the same time, the expression of two other genes (G6PD and tkt) in control glioma cells is re sistant to hypoxic treatment, but the expression level of TALDO1 and rPIA genes is decreased.…”

“…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]. In this study we demonstrated that the expres sion of most studied genes in control glioma cells is affected by hypoxia as compared to cells growing upon normoxic condition.…”

“…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].…”

Inhibition of ERN1 signaling enzyme affects hypoxic regulation

“…Moreover, hypoxia condition is associated to glioma development and locally induces an adaptive response which confers to tumor cells an enhanced survival and a more agressive behaviour. Hypoxia as well as the endoplasmic reticulum stress are important factors of malignant tumor growth and control of the expression of genes, which regulate numerous metabolic processes, cell proliferation and cancer growth [1][2][3][4][5]. The endoplasmic reticulum is a key organelle in the cellular response to different factors, which activate a complex set of signaling pathways named the unfolded protein response [1,6].…”

“…Hypoxia as well as the endoplasmic reticulum stress are important factors of malignant tumor growth and control of the expression of genes, which regulate numerous metabolic processes, cell proliferation and cancer growth [1][2][3][4][5]. The endoplasmic reticulum is a key organelle in the cellular response to different factors, which activate a complex set of signaling pathways named the unfolded protein response [1,6]. This adaptive response is activated upon the accumulation of misfolded proteins in the endoplasmic reticulum and is mediated by three endoplasmic reticulum-resident sensors named PERK (PRK-like ER kinase), ERN1 (Endoplasmic Reticulum to Nucleus signaling 1) also known as IRE1alpha (Inositol Requiring Enzyme-1α) and ATF6 (Activating Transcription Factor 6), however, ERN1 is the dominant component of this system [1,[7][8][9].…”