Minchenko O H, Kharkova A P, Minchenko D O, Karbovskyi L L
Ukr Biochem J. 2016 May-Jun;88(3):66-77. doi: 10.15407/ubj88.03.066.
We have studied gene expression of insulin-like growth factor binding proteins in U87 glioma cells upon glutamine deprivation depending on the inhibition of IRE1 (inositol requiring enzyme-1), a central mediator of endoplasmic reticulum stress. We have shown that exposure of control glioma cells upon glutamine deprivation leads to down-regulation of NOV/IGFBP9, WISP1 and WISP2 gene expressions and up-regulation of CYR61/IGFBP10 gene expression at the mRNA level. At the same time, the expression of IGFBP6 and IGFBP7 genes in control glioma cells was resistant to glutamine deprivation. It was also shown that the inhibition of IRE1 modifies the effect of glutamine deprivation on the expression of all studied genes. Thus, the inhibition of IRE1 signaling enzyme enhances the effect of glutamine deprivation on the expression of CYR61 and WISP1 genes and suppresses effect of the deprivation on WISP2 gene expression in glioma cells. Moreover, the inhibition of IRE1 introduces sensitivity of the expression of IGFBP6 and IGFBP7 genes to glutamine deprivation and removes this sensitivity to NOV gene. We have also demonstrated that the expression of all studied genes in glioma cells growing with glutamine is regulated by IRE1 signaling enzyme, because the inhibition of IRE1 significantly down-regulates IGFBP6 and NOV genes and up-regulates IGFBP7, CYR61, WISP1, and WISP2 genes as compared to control glioma cells. The present study demonstrates that glutamine deprivation condition affects most studied IGFBP and WISP gene expressions in relation to IRE1 signaling enzyme function and possibly contributes to slower glioma cell proliferation upon inhibition of IRE1.
我们研究了谷氨酰胺缺乏情况下，U87胶质瘤细胞中胰岛素样生长因子结合蛋白的基因表达，该过程依赖于内质网应激的核心介质肌醇需要酶1（IRE1）的抑制作用。我们发现，谷氨酰胺缺乏时，对照胶质瘤细胞的暴露导致NOV/IGFBP9、WISP1和WISP2基因表达在mRNA水平下调，CYR61/IGFBP10基因表达上调。同时，对照胶质瘤细胞中IGFBP6和IGFBP7基因的表达对谷氨酰胺缺乏具有抗性。研究还表明，IRE1的抑制改变了谷氨酰胺缺乏对所有研究基因表达的影响。因此，IRE1信号酶的抑制增强了谷氨酰胺缺乏对胶质瘤细胞中CYR61和WISP1基因表达的影响，并抑制了谷氨酰胺缺乏对WISP2基因表达的影响。此外，IRE1的抑制使IGFBP6和IGFBP7基因表达对谷氨酰胺缺乏产生敏感性，并消除了对NOV基因的这种敏感性。我们还证明，在谷氨酰胺存在下生长的胶质瘤细胞中，所有研究基因的表达都受IRE1信号酶调节，因为与对照胶质瘤细胞相比，IRE1的抑制显著下调了IGFBP6和NOV基因，并上调了IGFBP7、CYR61、WISP1和WISP2基因。本研究表明，谷氨酰胺缺乏条件会影响大多数研究的IGFBP和WISP基因表达，这与IRE1信号酶功能有关，并且在IRE1受到抑制时可能导致胶质瘤细胞增殖减缓。
