Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib

Berberich, Anne; Keßler, Tobias; Thomé, Carina M.; Pusch, Stefan; Hielscher, Thomas; Sahm, Felix; Oezen, Iris; Schmitt, Lara Marie; Ciprut, Sara; Hucke, Nanina; Ruebmann, Petra; Fischer, Manuel; Lemke, Dieter; Breckwoldt, Michael O.; Deimling, Andreas von; Bendszus, Martin; Platten, Michael; Wick, Wolfgang

doi:10.1158/1078-0432.ccr-18-1580

Cited by 46 publications

(49 citation statements)

References 41 publications

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“…The attenuation of p53 functions in GBM patients has been attributed to post-translational regulation of the p53 protein, whose levels are tightly controlled by the E3 ubiquitin ligase MDM2 through proteasomal degradation 28. Elevated levels of MDM2 protein impair wildtype p53 function and accelerate tumor growth in various human cancers, including leukemia, sarcoma, breast cancer, melanoma, and GBM 7, 29-32. Nevertheless, MDM2 also transfers ubiquitin to itself, resulting in self-destruction 6.…”

Section: Discussionmentioning

confidence: 99%

“…Although p53 can be produced constitutively, it is negatively regulated by the mouse double minute 2 (MDM2) protein that binds to the transcription activation domain of p53, thereby inhibiting acetylation, stimulating nuclear export, and most importantly, promoting proteasomal degradation via MDM2's E3 ubiquitin ligase activity 6. The tumor-promoting effect of MDM2 in GBMs has been reported in prior publications 7.…”

Section: Introductionmentioning

confidence: 97%

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MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas

et al. 2019

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Background: Glioblastoma (GBM) is highly proliferative and resistant to radio-chemotherapy. Loss of tumor suppressor gene TP53 function frequently occurs at protein level in GBMs. This inhibition is often mediated by other components within the p53 signaling axis, including MDM2, whose binding protein (MTBP) plays an important role in the regulation of MDM2 and p53 activity. We investigated the role of MTBP in the biology of TP53-wildtype (TP53wt) GBMs.Methods: MTBP expression was examined in TCGA and REMBRANDT datasets. MTBP was silenced or overexpressed in TP53wt GBM cells and glioma stem cells (GSCs). The effects on cell viability, apoptosis, and clonogenicity were assessed. The transcriptional regulation of MTBP was investigated.Results: Upregulation of MTBP was correlated with the Classical molecular subtype, and it predicted poor survival. In TP53wt GBM cells, the protein levels of MTBP were positively associated with those of MDM2 but negatively correlated with those of p53. MTBP knockdown promoted apoptosis and inhibited clonogenicity, while overexpression of this protein enhanced tumorigenicity in vitro and in vivo. The pro-survival effect of MTBP depended on the activity of MDM2 and p53. MTBP was transcriptionally regulated by c-myc, thereby forming a positive regulatory loop. Finally, MTBP silencing increased the sensitivity of TP53wt GSCs to radiation and TMZ treatment in vitro and in vivo.Conclusion: MTBP regulates the cell survival and treatment sensitivity of TP53wt GBMs through MDM2-dependent post-translational modification of p53. MTBP-targeting treatments are potentially useful in increasing patients' survival.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas

et al. 2019

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“…Although the DNA profile of the U87‐MG cells was found to be different from that of the original cells, it was likely a bona fide human GBM cell line of unknown origin . Many studies have successfully illustrated the pathogenesis of GBM and the pharmacological function of new pharmaceutical products on GBM with the U87‐MG cell line in recent years . In this study, we developed a concise and reliable analysis through combining our transcriptome analyses on U87‐MG and HEB cells with established databases and in vitro and ex vivo experiments, which successfully revealed a set of core pathways in GBM cells under normoxic and hypoxic conditions.…”

Section: Introductionmentioning

confidence: 99%

Integrated analysis identified core signal pathways and hypoxic characteristics of human glioblastoma

Gao

Zhang

Liu

et al. 2019

J Cellular Molecular Medi

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As a hallmark for glioblastoma (GBM), high heterogeneity causes a variety of phenotypes and therapeutic responses among GBM patients, and it contributes to treatment failure. Moreover, hypoxia is a predominant feature of GBM and contributes greatly to its phenotype. To analyse the landscape of gene expression and hypoxic characteristics of GBM cells and their clinical significance in GBM patients, we performed transcriptome analysis of the GBM cell line U87‐MG and the normal glial cell line HEB under normoxia and hypoxia conditions, with the results of which were analysed using established gene ontology databases as well as The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia. We revealed core signal pathways, including inflammation, angiogenesis and migration, and for the first time mapped the components of the toll‐like receptor 6 pathway in GBM cells. Moreover, by investigating the signal pathways involved in homoeostasis, proliferation and adenosine triphosphate metabolism, the critical response of GBM to hypoxia was clarified. Experiments with cell lines, patient serum and tissue identified IL1B, CSF3 and TIMP1 as potential plasma markers and VIM, STC1, TGFB1 and HMOX1 as potential biopsy markers for GBM. In conclusion, our study provided a comprehensive understanding for signal pathways and hypoxic characteristics of GBM and identified new biomarkers for GBM patients.

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“…in recent years, studies have reported the signaling pathway inhibitors have synergistic effects on radiotherapy and chemotherapy, which can significantly enhance the sensitivity of cancer therapy (27)(28)(29). lee et al (30) have demonstrated that lY294002 improves the sensitivity of cervical cancer cells to radiotherapy in a significant time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Tripartite motif‑containing 14 regulates cell proliferation and apoptosis in cervical cancer via the Akt signaling pathway

Diao

Guo

et al. 2020

Mol Med Rep

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Tripartite motif-containing (TriM) 14 is a protein of the TriM family. Studies have indicated that TriM14 may be used as an oncogene in tumor cells, such as osteosarcoma, non-small cell lung cancer and breast cancer through different pathways. However, the functions of TriM14 in cervical cancer cells remain unclear. Therefore, this study aimed to investigate the functions of TriM14 in cervical cancer cells and its underlying mechanism. caski cells stably expressing TriM14 and SiHa, and Hela cells stably expressing TriM14 short hairpin rna were constructed by lentivirus-mediated overexpression or knockdown systems. The effects of TriM14 on proliferation and apoptosis of cervical cancer cells were detected by cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. in addition, reverse transcription-quantitative (rT-q) Pcr and western blotting were used to investigate the expression levels of TriM14 and of signaling pathway marker protein including P21, caspase-3, cleaved caspase-3, akt and phosphorylated akt. The results of rT-qPcr and western blotting revealed that TriM14 was highly expressed in human cervical cancer tissues and cell lines compared with adjacent normal tissues and normal cervical epithelial cells. TriM14 also regulated cell proliferation and apoptosis of human SiHa, Hela and caski cervical cancer cell lines through the akt signaling pathway. additionally, TriM14 protein levels were related to the clinical and pathological features of cervical cancer. CCK-8 assay and flow cytometry demonstrated that TRIM14 expression could promote cervical cancer cell proliferation and autophagy suppression. Taken together, TriM14-induced cell proliferation and apoptosis inhibition may by evoked by the activation of the akt pathway. This study demonstrated the role of TriM14 in cervical cancer, and reveals its mechanism of action as a potential therapeutic target for cervical cancer.

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Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib

Cited by 46 publications

References 41 publications

MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas

MTBP regulates cell survival and therapeutic sensitivity in TP53 wildtype glioblastomas

Integrated analysis identified core signal pathways and hypoxic characteristics of human glioblastoma

Tripartite motif‑containing 14 regulates cell proliferation and apoptosis in cervical cancer via the Akt signaling pathway

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