Abstract
We have studied the effect of hypoxia on the expression of nuclear genes encoding mitochondrial proteins in U87 glioma cells under the inhibition of IRE1 (inositol requiring enzyme-1), which controls cell proliferation and tumor growth as a central mediator of endoplasmic reticulum stress. It was shown that hypoxia down-regulated gene expression of malate dehydrogenase 2 (MDH2), malic enzyme 2 (ME2), mitochondrial aspartate aminotransferase (GOT2), and subunit B of succinate dehydrogenase (SDHB) in control (transfected by empty vector) glioma cells in a gene specific manner. At the same time, the expression level of mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) and subunit D of succinate dehydrogenase (SDHD) genes in these cells does not significantly change in hypoxic conditions. It was also shown that the inhibition of ІRE1 signaling enzyme function in U87 glioma cells decreases the effect of hypoxia on the expression of ME2, GOT2, and SDHB genes and introduces the sensitivity of IDH2 gene to hypoxia. Furthermore, the expression of all studied genes depends on IRE1-mediated endoplasmic reticulum stress signaling in gene specific manner, because ІRE1 knockdown significantly decreases their expression in normoxic conditions, except for IDH2 gene, which expression level is strongly up-regulated. Therefore, changes in the expression level of nuclear genes encoding ME2, MDH2, IDH2, SDHB, SDHD, and GOT2 proteins possibly reflect metabolic reprogramming of mitochondria by hypoxia and IRE1-mediated endoplasmic reticulum stress signaling and correlate with suppression of glioma cell proliferation under inhibition of the IRE1 enzyme function.
Highlights
Mitochondria play an important role in the regulation of tumor growth and apoptosis through numerous metabolic pathways [1,2,3]
Mitochondrial NAD-dependent malic enzyme (ME2) that catalyzes the oxidative decarboxylation of malate to pyruvate is a target of TP53 depletion of this enzyme, induces erythroid differentiation in human erythroleukemia cells [16, 17]
We have studied the effect of hypoxia on the expression of nuclear genes encoding mitochondrial proteins malic enzyme 2 (ME2), malate dehydrogenase 2 (MDH2), isocitrate dehydrogenase 2 (IDH2), SDHB, succinate dehydrogenase (SDHD), and GOT2 in two sublines of U87 glioma cells in relation to inhibition of IRE1 signaling enzyme, which is a major component of the unfolded protein response
Summary
Mitochondria play an important role in the regulation of tumor growth and apoptosis through numerous metabolic pathways [1,2,3]. It was shown that inhibition of IRE1 (inositol requiring enzyme 1) which represents a dominant signaling pathway of the unfolded protein response, modifies hypoxic regulation of ENDOG, POLG, TSFM, and MTIF2 genes expression [5]. The malate-aspartate shuttle is indispensable for the net transfer of cytosolic NADH into mitochondria to maintain a high rate of glycolysis and to support rapid tumor cell growth [20] It is done by two pairs of enzymes that locali ze to the mitochondria and cytoplasm, glutamate oxaloacetate transaminases (GOT), and malate dehydrogenases (MDH). It was shown that IDH2 plays an essential role in protecting cells against oxidative stress-induced damage and this enzyme deficiency leads to mitochondrial dysfunction and production of reactive oxygen species in cancer cells [24]. A better knowledge of tumor responses to hypoxia is required to elaborate therapeutical strategies of cell sensibilization based on the blockade of survival mechanisms [9, 29]
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