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Wild?type IDH1 affects cell migration by modulating the PI3K/AKT/mTOR pathway in primary glioblastoma cells.

ABSTRACT: Glioblastoma (GBM) is the most common type of brain cancer and has the highest mortality. Dysregulated expression of wild?type isocitrate dehydrogenase 1 (IDH1) has been demonstrated to promote the progression of primary GBM without accumulating D?2?hydroxyglutarate, which differs from IDH1 mutation?related mechanisms of tumorigenesis. Previous studies have revealed several roles of wild?type IDH1 in primary GBM, involving proliferation and apoptosis. However, the function of IDH1 in cell migration has not been investigated. In the current study, the results of bioinformatics analysis revealed that IDH1 expression was significantly upregulated in patients with primary GBM. Wound healing and Transwell assays demonstrated that IDH1 overexpression promoted cell migration in primary GBM cells and that IDH1 knockdown hindered this process. Furthermore, ??ketoglutarate (??KG), which is the main product of IDH1?catalyzed reactions, was significantly decreased by IDH1 knockdown and upregulated by IDH1 overexpression. ??KG treatment significantly increased the migration of primary GBM cells. Additionally, RNA sequence analysis of patients with primary GBM reported significant alterations in the expression of phosphoinositide 3?kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway?regulated genes, including Myc, Snail family transcriptional repressor 2 and Twist?related protein 1, which are primarily cell migration regulatory factors. Western blotting revealed that the overexpression or knockdown of IDH1 promoted or inhibited the PI3K/AKT/mTOR pathway, respectively. ??KG treatment of primary GBM cells also promoted the PI3K/AKT/mTOR pathway. Furthermore, IDH1?overexpressing and ??KG?treated U87 cells were incubated with rapamycin, an mTOR?specific inhibitor, and the results revealed that rapamycin treatment reversed the increased cell migration caused by IDH1 overexpression and ??KG treatment. The results indicated that IDH1 regulated the migration of primary GBM cells by altering ??KG levels and that the function of the IDH1/??KG axis may rely on PI3K/AKT/mTOR pathway regulation.

SUBMITTER: Shen X

PROVIDER: S-EPMC7411459 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Wild‑type IDH1 affects cell migration by modulating the PI3K/AKT/mTOR pathway in primary glioblastoma cells.

Shen Xiaopeng X Wu Shen S Zhang Jingyi J Li Meng M Xu Feng F Wang Ao A Lei Yang Y Zhu Guoping G

Molecular medicine reports 20200618 3

Glioblastoma (GBM) is the most common type of brain cancer and has the highest mortality. Dysregulated expression of wild‑type isocitrate dehydrogenase 1 (IDH1) has been demonstrated to promote the progression of primary GBM without accumulating D‑2‑hydroxyglutarate, which differs from IDH1 mutation‑related mechanisms of tumorigenesis. Previous studies have revealed several roles of wild‑type IDH1 in primary GBM, involving proliferation and apoptosis. However, the function of IDH1 in cell migrat ...[more]

PMID: 32705169

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Project description:Glioblastoma is a high-grade glioma with poor prognosis even after surgery and standard therapy. Here, we asked whether carnosine (β-alanyl-L-histidine), a naturally occurring dipeptide, exert its anti-neoplastic effect on glioblastoma cells via PI3K/Akt/mTOR signaling. Therefore, glioblastoma cells from the lines U87 and T98G were exposed to carnosine, to the mTOR inhibitor rapamycin and to the PI3K inhibitor Ly-294,002. Pyruvate dehydrogenase kinase (PDK4) expression, known to be a target of PI3K/Akt/mTOR, and which is also affected by carnosine, was analyzed by RT-qPCR, and reporter gene assays with the human PDK4 promoter were performed. Cell viability was assessed by cell-based assays and mTOR and Akt phosphorylation by Western blotting. Rapamycin and Ly-294,002 increased PDK4 mRNA expression in both cell lines but significance was only reached in U87. Carnosine significantly increased expression in both lines. A significant combinatorial effect of carnosine was only detected in U87 when the dipeptide was combined with Ly-294,002. Reporter gene assays revealed no specific effect of carnosine on the human PDK4 promoter, whereas both inhibitors increased reporter gene expression. Rapamycin reduced phosphorylation of mTOR, and Ly-294,002 that of Akt. A significant reduction of Akt phosphorylation was observed in the presence of carnosine in U87 but not in T98G, and carnosine had no effect on mTOR phosphorylation. Cell viability as determined by ATP in cell lysates was reduced only in the presence of carnosine. We conclude that carnosine's anti-neoplastic effect is independent from PI3K/Akt/mTOR signaling. As the dipeptide reduced viability in tumor cells that do not respond to PI3K or mTOR inhibitors, it appears to be worth to further investigate the mechanisms by which carnosine exerts its anti-tumor effect and to consider it for therapy, especially as it is a naturally occurring compound that has already been used for the treatment of other diseases without indication of side-effects.

Project description:BackgroundPreeclampsia (PE) is a complex pregnancy-related disease that endangers the safety of maternal and fetal. The purpose of this study is to reveal the pathogenesis of preeclampsia and discover new predictors from the perspective of peptidomics. The umbilical cord blood of PE and control group was analyzed by peptidomics. A peptide named Regulation of Proliferation Process in Preeclampsia (ROPPIP) was screened out to explore its role in the proliferation, migration and apoptosis of trophoblast cells in preeclampsia.MethodsWe compared and analyzed the umbilical cord blood of patients with PE and normal pregnant women using liquid chromatography-tandem mass spectrometry (LC-MS). hTR-8/Svneo cells cultured in vitro were divided into ROPPIP group and a disordered peptide group as control. Cell Counting Kit-8 (CCK-8) assay, flow cytometry, Transwell chamber assays and western blot analysis were performed to detect cell proliferation, invasion, migration and apoptosis, in addition to the expression of Matrix metalloproteinase-2 (MMP2), nuclear associated antigen Ki67, B-cell lymphoma-2 (Bcl2), Caspase 3, and β-actin protein.ResultsWe identified 133 differential peptides. Of these, 51 were up-regulated while 82 were down-regulated. the polypeptide SFGVRMATASPTDGNV with low differential expression in the serum of PE patients was selected for the study, we named the polypeptide as Regulation of Proliferation Process in PE (ROPPIP). The experiment shows that ROPPIP can up-regulate the expression levels of MMP2, Ki67, and Bcl2 in HTR-8/Svneo cells, down-regulate the expression of caspase-3, promote the proliferation and migration of HTR-8/Svneo cells and inhibit the apoptosis induced by cisplatin, the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway may be associated with the function of ROPPIP.ConclusionsROPPIP promotes HTR-8/Svneo cells migration and proliferation, and inhibits apoptosis, by regulating the activation of the PI3K/AKT/mTOR signaling pathway.

Dataset Information

Wild?type IDH1 affects cell migration by modulating the PI3K/AKT/mTOR pathway in primary glioblastoma cells.

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Wild‑type IDH1 affects cell migration by modulating the PI3K/AKT/mTOR pathway in primary glioblastoma cells.

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