Abstract
Inhibition of IRE1 (inositol requiring enzyme-1), the major signaling pathway of endoplasmic reticulm stress, significantly decreases glioma cell proliferation and tumor growth. We have studied the expression of TNFα-related genes and effect of glucose deprivation on these gene expressions in U87 glioma cells over-expressing dominant-negative IRE1 defective in both kinase and endonuclease (dn-IRE1) activity of IRE1 with hopes of elucidating its contribution to IRE1 mediated glioma growth. We have demonstrated that glucose deprivation condition leads to down-regulation of the expression of TNFRSF11B, TNFRSF1A, TNFRSF10D/TRAILR4, and LITAF genes and up-regulation of TNFRSF10B/TRAILR2/DR5 gene at the mRNA level in control glioma cells. At the same time, the expression of TNFRSF21/DR6, TNFAIP1, TNFAIP3, TRADD, and CD70/TNFSF7 genes in control glioma cells is resistant to glucose deprivation condition. The inhibition of IRE1 modifies the effect of glucose deprivation on LITAF, TNFRSF21, TNFRSF11B, and TRADD gene expressions and induces sensitivity to glucose deprivation condition the expression of TNFRSF10B, TNFRSF1A, and CD70 genes. We have also demonstrated that the expression of all studied genes is affected in glioma cells by inhibition of IRE1, except TNFRSF1A gene, as compared to control glioma cells. Moreover, the changes in the expression of TNFRSF1A, TNFRSF10D/TRAILR4, and LITAF genes induced by glucose deprivation condition have opposite orientation to that induced by inhibition of IRE1. The present study demonstrates that fine-tuning of the expression of TNFα-induced proteins and TNF receptor superfamily genes, which related to cell death and proliferation, is regulated by IRE1, an effector of endoplasmic reticulum stress, as well as depends on glucose deprivation in gene specific manner. Thus, the inhibition of kinase and endoribonuclease activity of IRE1 correlates with deregulation of TNFα-induced protein genes and TNF receptor superfamily genes in gene specific manner and thus slower the tumor growth.
Highlights
Inhibition of IRE1, the major signaling pathway of endoplasmic reticulum stress, significantly decreases glioma cell proliferation and tumor growth
We have demonstrated that glucose deprivation condition leads to down-regulation of the expression of TNFRSF11B, TNFRSF1A, TNFRSF10D/ TNF-related apoptosis-inducing ligand receptor 4 (TRAILR4), and LITAF genes and up-regulation of TNFRSF10B/TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2)/death receptor 5 (DR5) gene at the mRNA level in control glioma cells
The aim of this study was to investigate the effects of glucose deprivation on the expression of genes encoding for tumor necrosis factor receptor superfamily and TNFα induced proteins, which participate in the regulation of apoptosis and cell proliferation, in glioma cells, as well as the contribution of endoplasmic reticulum stress sensor IRE1 to fine tune their expression with hopes of elucidating its role in the progression of certain cancers
Summary
Inhibition of IRE1 (inositol requiring enzyme-1), the major signaling pathway of endoplasmic reticulum stress, significantly decreases glioma cell proliferation and tumor growth. The present study demonstrates that fine-tuning of the expression of TNFα-induced proteins and TNF receptor superfamily genes, which related to cell death and proliferation, is regulated by IRE1, an effector of endoplasmic reticulum stress, as well as depends on glucose deprivation in gene specific manner. The rapid growth of solid tumors generates micro-environmental changes in association to hypoxia, nutrient deprivation and acidosis, which induce formation of new blood vessels and cell proliferation and surviving [2, 3, 5] Those processes rely on the activation of endoplasmic reticulum stress signalling pathways [2, 3]. Activation of the IRE1 branch of the endoplasmic reticulum stress response is intimately linked to apoptosis The ablation of this sensor’s function by a dominant-negative construct of IRE1 (dn-IRE1) has been shown to result in a significant anti-proliferative effect in glioma growth [2, 10, 16]. It is becoming increasingly clear that death receptor engagement, especially in the context of cancer, can lead to outcomes, other than apoptosis, that become subverted by certain tumors to their benefit [23, 25, 30]
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