Dataset Information

Overexpressed GNA13 induces temozolomide sensitization via down-regulating MGMT and p-RELA in glioma.

ABSTRACT: Temozolomide (TMZ), one of the few effective drugs used during adjuvant therapy, could effectively prolong the overall survival (OS) of glioma patients. In our previous study, the mRNA level of G Protein Subunit Alpha 13 (GNA13) was found to be inversely correlated with OS and was therefore identified as a potential biomarker for the prognosis of glioma. Henceforth, this study aims to identify the molecular mechanism of GNA13 in enhancing TMZ sensitization through bioinformatic analyses of GSE80729 and GSE43452 and other experiments. In glioma, overexpression of GNA13 downregulated PRKACA, which is a subunit of PKA, hence reducing phosphorylated RELA and MGMT. Since p-RELA and MGMT were proven to be closely associated with TMZ resistance, we therefore investigated whether thetwo signaling pathways, "GNA13/PRKACA/p-RELA", and "GNA13/PRKACA/MGMT", were involved in the molecular mechanism of GNA13 in TMZ sensitization. Our conclusion was that, GNA13 overexpression in glioma cells were more sensitive in TMZ treatment.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8581860 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Overexpressed GNA13 induces temozolomide sensitization via down-regulating MGMT and p-RELA in glioma.

Liu Yan Y Du Zepeng Z Xu Zhennan Z Jin Tao T Xu Ke K Huang Meihui M Wang Shaohong S Zheng Yuyu Y Liu Mingfa M Xu Haixiong H

American journal of translational research 20211015 10

Temozolomide (TMZ), one of the few effective drugs used during adjuvant therapy, could effectively prolong the overall survival (OS) of glioma patients. In our previous study, the mRNA level of G Protein Subunit Alpha 13 (GNA13) was found to be inversely correlated with OS and was therefore identified as a potential biomarker for the prognosis of glioma. Henceforth, this study aims to identify the molecular mechanism of GNA13 in enhancing TMZ sensitization through bioinformatic analyses of GSE80 ...[more]

PMID: 34786068

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Project description:BackgroundHigh-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation. This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas.MethodsU251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, tumor cell spheroid growth, and colony formation assay. Cell apoptosis and cell cycle were detected by flow cytometry. Temozolomide (TMZ)-insensitive cell lines were induced by long-term TMZ treatment, and cells with stem cell characteristics were enriched with stem cell culture medium. The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction, and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections. Via inoculating U87 cells subcutaneously, glioma xenograft models in nude mice were established for drug experiments. Patient survival data were analyzed using the Kaplan-Meier method.ResultsBortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest. Bortezomib also significantly inhibited the spheroid growth, colony formation, and stem-like cell proliferation of U251 and U87 cells. When administrated in combination, bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo. Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1 (FOXM1) and its target gene Survivin. The FOXM1-Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients. Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor prognosis in glioma patients.ConclusionsBortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy, probably via down-regulating the FOXM1-Survivin axis. Bortezomib might be a promising agent for treating malignant glioma, alone or in combination with TMZ.

Project description:Prior studies implicate type 1 IGF receptor (IGF-1R) in mediating chemo-resistance. Here, we investigated whether IGF-1R influences response to temozolomide (TMZ), which generates DNA adducts that are removed by O6-methylguanine-DNA methyltransferase (MGMT), or persist causing replication-associated double-strand breaks (DSBs). Initial assessment in 10 melanoma cell lines revealed that TMZ resistance correlated with MGMT expression (r = 0.79, p = 0.009), and in MGMT-proficient cell lines, with phospho-IGF-1R (r = 0.81, p = 0.038), suggesting that TMZ resistance associates with IGF-1R activation. Next, effects of IGF-1R inhibitors (IGF-1Ri) AZ3801 and linsitinib (OSI-906) were tested on TMZ-sensitivity, cell cycle progression and DSB induction. IGF-1Ri sensitized BRAF wild-type and mutant melanoma cells to TMZ in vitro, an effect that was independent of MGMT. Cells harboring wild-type p53 were more sensitive to IGF-1Ri, and showed schedule-dependent chemo-sensitization that was most effective when IGF-1Ri followed TMZ. This sequence sensitized to clinically-achievable TMZ concentrations and enhanced TMZ-induced apoptosis. Simultaneous or prior IGF-1Ri caused less effective chemo-sensitization, associated with increased G1 population and reduced accumulation of TMZ-induced DSBs. Clinically relevant sequential (TMZ → IGF-1Ri) treatment was tested in mice bearing A375M (V600E BRAF, wild-type p53) melanoma xenografts, achieving peak plasma/tumor IGF-1Ri levels comparable to clinical Cmax, and inducing extensive intratumoral apoptosis. TMZ or IGF-1Ri caused minor inhibition of tumor growth (gradient reduction 13%, 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from control (p < 0.01), TMZ (p < 0.01) and IGF-1Ri (p < 0.05) groups. These data highlight the importance of scheduling when combining IGF-1Ri and other targeted agents with drugs that induce replication-associated DNA damage.

Dataset Information

Overexpressed GNA13 induces temozolomide sensitization via down-regulating MGMT and p-RELA in glioma.

Publications

Overexpressed GNA13 induces temozolomide sensitization via down-regulating MGMT and p-RELA in glioma.

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