Overexpressed GNA13 induces temozolomide sensitization via down-regulating MGMT and p-RELA in glioma
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ABSTRACT:
SUBMITTER: Liu Y
PROVIDER: S-EPMC8581860 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Preliminary studies have shown that endothelial-monocyte-activating polypeptide-II (EMAP-II) and temozolomide (TMZ) alone can exert cytotoxic effects on glioma cells. This study explored whether EMAP-II can enhance the cytotoxic effects of TMZ on glioma stem cells (GSCs) and the possible mechanisms associated with Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-mediated mitophagy facilitated by miR-24-3p regulation. The combination of TMZ and EMAP-II significantly inhibited GSCs viability, migration, and invasion, resulting in upregulation of the autophagy biomarker microtubule-associated protein one light chain 3 (LC3)-II/I but down-regulation of the proteins P62, TOMM 20 and CYPD, changes indicative of the occurrence of mitophagy. BNIP3 expression increased significantly in GSCs after treatment with the combination of TMZ and EMAP-II. BNIP3 overexpression strengthened the cytotoxic effects of EMAP-II and TMZ by inducing mitophagy. The combination of EMAP-II and TMZ decreased the expression of miR-24-3p, whose target gene was BNIP3. MiR-24-3p inhibited mitophagy and promoted proliferation, migration and invasion by down-regulating BNIP3 in GSCs. Furthermore, nude mice subjected to miR-24-3p silencing combined with EMAP-II and TMZ treatment displayed the smallest tumors and the longest survival rate. According to the above results, we concluded that EMAP-II enhanced the cytotoxic effects of TMZ on GSCs' proliferation, migration and invasion both in vitro and in vivo.
| S-EPMC5879952 | biostudies-literature
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.
| S-EPMC6892143 | biostudies-literature
Project description: Not available
| S-EPMC2940592 | biostudies-literature
Project description:BackgroundTemozolomide (TMZ) is a first-line chemotherapy drug for the treatment of malignant glioma and resistance to it poses a major challenge. Receptor-interacting protein 2 (RIP2) is associated with the malignant character of cancer cells. However, it remains unclear whether RIP2 is involved in TMZ resistance in glioma.MethodsRIP2 expression was inhibited in TMZ-resistant glioma cells and normal glioma cells by using small interfering RNA (siRNA) against RIP2. Plasmid transfection method was used to overexpress RIP2. Cell counting kit-8 assays were performed to evaluate cell viability. Western blotting or immunofluorescence was performed to determine RIP2, NF-κB, and MGMT expression in cells. Flow cytometry was used to investigate cell apoptosis. TMZ-resistant glioma xenograft models were established to evaluate the role of the RIP2/NF-κB/MGMT signaling pathway in drug resistance.ResultsWe observed that RIP2 expression was upregulated in TMZ-resistant glioma cells, whereas silencing of RIP2 expression enhanced cellular sensitivity to TMZ. Similarly, upon the induction of RIP2 overexpression, glioma cells developed resistance to TMZ. The molecular mechanism underlying the process indicated that RIP2 can activate the NF-κB signaling pathway and upregulate the expression of O6-methylguanine-DNA methyltransferase (MGMT), following which the glioma cells develop drug resistance. In the TMZ-resistant glioma xenograft model, treatment with JSH-23 (an NF-κB inhibitor) and lomeguatrib (an MGMT inhibitor) could enhance the sensitivity of the transplanted tumor to TMZ.ConclusionWe report that the RIP2/NF-κB/MGMT signaling pathway is involved in the regulation of TMZ resistance. Interference with NF-κB or MGMT activity could constitute a novel strategy for the treatment of RIP2-positive TMZ-resistant glioma.
| S-EPMC8025621 | biostudies-literature
Project description:The heterogeneous molecular subtypes of gliomas demonstrate varied responses to chemotherapy and distinct prognostic outcomes. Gliomas with Isocitrate dehydrogenase 1 (IDH1) mutation are associated with better outcomes and are more responsive to temozolomide (TMZ) compared to those without IDH1 mutation. IDH1-mutant gliomas elevate D-2-hydroxyglutarate (D-2HG) levels, with potential dual effects on tumor progression. Limited research has explored the potential anti-glioma effects of D-2HG in combination with TMZ. Clinical data from over 2500 glioma patients in our study confirms that those with IDH1 mutations exhibit enhanced responsiveness to TMZ chemotherapy and a significantly better prognosis compared to IDH1 wild-type patients. In subsequent cellular experiments, we found that the IDH1-mutant metabolite D-2HG suppresses Integrin subunit beta 4 (ITGB4) expression, and down-regulate the phosphorylation levels of PI3K and AKT, ultimately inhibiting cell proliferation while promoting apoptosis, thereby improving glioma prognosis. Additionally, we have demonstrated the synergistic effect of D-2HG and TMZ in anti-glioma therapy involved inhibiting the proliferation of glioma cells and promoting apoptosis. Finally, by integrating data from the CGGA and TCGA databases, it was validated that ITGB4 expression was lower in IDH1-mutant gliomas, and patients with lower ITGB4 expression were associated with better prognosis. These findings indicate that ITGB4 may be a promising therapeutic target for gliomas and D-2HG inhibits proliferation and sensitizes glioma to temozolomide via down-regulating ITGB4/PI3K/AKT. These findings drive theoretical innovation and research progress in glioma therapy.
| S-EPMC11233597 | biostudies-literature
Project description:Temozolomide (TMZ) is a conventional chemotherapeutic drug for glioma, however, its clinical application and efficacy is severely restricted by its drug resistance properties. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme, which can repair the DNA damage caused by TMZ. A large number of clinical data show that reducing the expression of MGMT can enhance the chemotherapeutic efficacy of TMZ. Therefore, in order to improve the resistance of glioma to TMZ, an angiopep-2 (A2) modified nanoprodrug of polytemozolomide (P(TMZ)n) that combines with MGMT siRNA (siMGMT) targeting MGMT was developed (A2/T/D/siMGMT). It not only increased the amount of TMZ within tumor lesion site, but also reduced MGMT expression in glioma. The in vitro experiments indicated that the A2/T/D/siMGMT effectively enhanced the cellular uptake of TMZ and siMGMT, and resulted in a significant cell apoptosis and cytotoxicity in the glioma cells. The in vivo experiments showed that glioma growth was inhibited and the survival time of animals were prolonged remarkably after A2/T/D/siMGMT was injected via tail vein. The results showed that the therapeutic effect of A2/T/D/siMGMT in the treatment of glioma was significantly improved.
| S-EPMC9809344 | biostudies-literature
Project description:Chemo-resistance hinders the therapeutic efficacy of temozolomide (TMZ) in treating glioblastoma multiforme (GBM). Recurrence of GBM even after combination of maximal tumor resection, concurrent radio-chemotherapy, and systemic TMZ applocation is inevitable and attributed to the high therapeutic resistance of glioma stem cells (GSCs), which can survive, evolve, and initiate tumor tissue remodeling, the underlying mechanisms of GSCs chemo-resistance, have not been fully elucidated up-to-now. Emerging evidence showed that METTL3-mediated N6-methyladenosine (m6A) modification contributed to the self-renew and radio-resistance in GSCs, however, its role on maintenance of TMZ resistance of GSCs has not been clarified and need further investigations. We found that the cell viability and half-maximal inhibitory concentration (IC50) of GSCs against TMZ significantly decreased after GSCs underwent serum-induced differentiation to adherent growth of tumor cells. Besides, METTL3 expression and total m6A modification declined dramatically in consistence with GSCs differentiation. Knockdown of METTL3 weakened self-renew, proliferation and TMZ IC50 of GSCs, whereas enhanced TMZ induced γH2AX level, indicating upregulation of double-strand DNA damage. We also found that mRNA stability of two critical DNA repair genes (MGMT and APNG) was regulated by METTL3-mediated m6A modification. In conclusion, we speculated that METTL3-mediated m6A modification of MGMT and APNG mRNAs played crucial roles on suppression of TMZ sensitivity of GSCs, which suggest a potential new therapeutic target of METTL3 against GBM.
| S-EPMC9868123 | biostudies-literature
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.
| S-EPMC4741867 | biostudies-other
Project description:Genotoxic chemotherapy with temozolomide (TMZ) is a mainstay of treatment for glioblastoma (GBM); however, at best, TMZ provides only modest survival benefit to a subset of patients. Recent insight into the heterogeneous nature of GBM suggests a more personalized approach to treatment may be necessary to overcome cancer drug resistance and improve patient care. These include novel therapies that can be used both alone and with TMZ to selectively reactivate apoptosis within malignant cells. For this approach to work, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified first. Here, we describe the first proof-of-principle study that merges quantitative protein-based analysis of apoptosis signaling networks with data- and knowledge-driven mathematical systems modeling to predict treatment responsiveness of GBM cell lines to various apoptosis-inducing stimuli. These include monotherapies with TMZ and TRAIL, which activate the intrinsic and extrinsic apoptosis pathways, respectively, as well as combination therapies of TMZ+TRAIL. We also successfully employed this approach to predict whether individual GBM cell lines could be sensitized to TMZ or TRAIL via the selective targeting of Bcl-2/Bcl-xL proteins with ABT-737. Our findings suggest that systems biology-based approaches could assist in personalizing treatment decisions in GBM to optimize cell death induction.
| S-EPMC5308652 | biostudies-literature
Project description:Acquired resistance of temozolomide (TMZ) is one of the major obstacle of glioblastoma clinical treatment and the mechanism of TMZ resistance is still not very clear. In the presented research we show that deletion of rs16906252-associated MGMT enhancer in MGMT negative glioma cells induced increase sensitivity to temozolomide and combination of RNA-seq and Capture HiC identified several long-range target genes of rs16906252-associated MGMT enhancer. In addition, HiC data shows alterations of chromatin structures in glioma cells survived from high-dosage TMZ treatment and changes of TADs influence rs16906252-associated MGMT enhancer’s long-range regulations of target genes. Our study suggests rs16906252-associated MGMT enhancer regulates glioma cells’ TMZ sensitivity by long-range regulations of several target genes, which is a novel mechanism of regulation of TMZ sensitivity in glioma cells.
2020-04-02 | GSE129476 | GEO