Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

De, Kuntal; Grubb, Treg; Zalenski, Abigail A.; Pfaff, Kayla E.; Pal, Debjani; Majumder, Shubhra; Summers, Matthew K.; Venere, Monica

doi:10.1158/1541-7786.mcr-18-1361

Cited by 26 publications

(17 citation statements)

References 57 publications

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“…Anaphase-Promoting Complex (APC/C) inhibitors, such as proTAME and apcin, targeted cell cycle proteins for proteasomal-mediated degradation. The targets of APC/C are regulated throughout the cell cycle via two mutually exclusive activator proteins, CDH1 and CDC20 [ 31 ]. W-13 is a calmodulin antagonist that could inhibit cell growth and induce cell apoptosis, which may display antitumor effects by binding to CAMK2G protein [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

[Retracted] Potential Drug Prediction of Glioblastoma Based on Drug Perturbation‐Induced Gene Expression Signatures

Zhu

Mao

Man

2021

BioMed Research International

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Objectives. Glioblastoma (GBM) is a malignant brain tumor which is the most common and aggressive type of central nervous system cancer, with high morbidity and mortality. Despite lots of systematic studies on the molecular mechanism of glioblastoma, the pathogenesis is still unclear, and effective therapies are relatively rare with surgical resection as the frequently therapeutic intervention. Identification of fundamental molecules and gene networks associated with initiation is critical in glioblastoma drug discovery. In this study, an approach for the prediction of potential drug was developed based on perturbation-induced gene expression signatures. Methods. We first collected RNA-seq data of 12 pairs of glioblastoma samples and adjacent normal samples from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by DESeq2, and coexpression networks were analyzed with weighted gene correlation network analysis (WGCNA). Furthermore, key driver genes were detected based on the differentially expressed genes and potential chemotherapeutic drugs and targeted drugs were found by correlating the gene expression profiles with drug perturbation database. Finally, RNA-seq data of glioblastoma from The Cancer Genome Atlas (TCGA) dataset was collected as an independent validation dataset to verify our findings. Results. We identified 1771 significantly DEGs with 446 upregulated genes and 1325 downregulated genes. A total of 24 key drivers were found in the upregulated gene set, and 81 key drivers were found in the downregulated gene set. We screened the Crowd Extracted Expression of Differential Signatures (CREEDS) database to identify drug perturbations that could reverse the key factors of glioblastoma, and a total of 354 drugs were obtained with p value < 10-10. Finally, 7 drugs that could turn down the expression of upregulated factors and 3 drugs that could reverse the expression of downregulated key factors were selected as potential glioblastoma drugs. In addition, similar results were obtained through the analysis of TCGA as independent dataset. Conclusions. In this study, we provided a framework of workflow for potential therapeutic drug discovery and predicted 10 potential drugs for glioblastoma therapy.

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Section: Discussionmentioning

confidence: 99%

[Retracted] Potential Drug Prediction of Glioblastoma Based on Drug Perturbation‐Induced Gene Expression Signatures

Zhu

Mao

Man

2021

BioMed Research International

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“…The inhibitory effect of proTAME on APC/C activity also seems to have great therapeutic potential. In combination with other inhibitors, proTAME was shown to be efficient in overcoming resistance caused by the hyperphosphorylation of CDH1 in glioblastoma cells [9], polo-like kinase 1 (PLK1)-based drug resistance in ovarian cancer cells [10] and CDC20-based resistance in diffuse large B-cell lymphoma [11].…”

Section: Introductionmentioning

confidence: 99%

ProTAME Arrest in Mammalian Oocytes and Embryos Does Not Require Spindle Assembly Checkpoint Activity

Radonova

Svobodova

Skultety

et al. 2019

IJMS

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In both mitosis and meiosis, metaphase to anaphase transition requires the activity of a ubiquitin ligase known as anaphase promoting complex/cyclosome (APC/C). The activation of APC/C in metaphase is under the control of the checkpoint mechanism, called the spindle assembly checkpoint (SAC), which monitors the correct attachment of all kinetochores to the spindle. It has been shown previously in somatic cells that exposure to a small molecule inhibitor, prodrug tosyl-l-arginine methyl ester (proTAME), resulted in cell cycle arrest in metaphase, with low APC/C activity. Interestingly, some reports have also suggested that the activity of SAC is required for this arrest. We focused on the characterization of proTAME inhibition of cell cycle progression in mammalian oocytes and embryos. Our results show that mammalian oocytes and early cleavage embryos show dose-dependent metaphase arrest after exposure to proTAME. However, in comparison to the somatic cells, we show here that the proTAME-induced arrest in these cells does not require SAC activity. Our results revealed important differences between mammalian oocytes and early embryos and somatic cells in their requirements of SAC for APC/C inhibition. In comparison to the somatic cells, oocytes and embryos show much higher frequency of aneuploidy. Our results are therefore important for understanding chromosome segregation control mechanisms, which might contribute to the premature termination of development or severe developmental and mental disorders of newborns.

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“…The binding site of Apcin on Cdc20 has been identified [ 19 ] and a study on SAR has revealed that the pyrimidine ring and aminal nitrogens, together with the hydrophobic trichloromethyl group, are important structural motifs; in contrast, the elimination of the nitro-imidazole moiety produces little effect. Apcin showed preclinical activity against multiple myeloma [ 26 ], prostate cancer [ 27 ], glioblastoma [ 28 ] and osteosarcoma [ 29 ] cells. Very recently, during the current investigation, the synthesis and the in vitro evaluation in a panel of solid tumor cells [MCF-7, A375, A549, HepG2, Hela, Ovcar-3 and Caov-3) of a series of 2,2,2-trichloro-1-aryl carbamate derivatives in which Apcin was modified by changing the pyrimidinyl or the 1-(2-methoxyethyl)-2-methyl-5-nitro-1H-imidazolyl moiety, has been reported [ 30 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Novel Tryptamine Derivatives and Their Biological Activity as Antitumor Agents

et al. 2021

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We synthesized five novel tryptamine derivatives characterized by the presence of an azelayl chain or of a 1,1,1-trichloroethyl group, in turn connected to another heterocyclic scaffold. The combination of tryptamin-, 1,1,1-trichloroethyl- and 2-aminopyrimidinyl- moieties produced compound 9 identified as the most active compound in hematological cancer cell lines (IC50 = 0.57–65.32 μM). Moreover, keeping constant the presence of the tryptaminic scaffold and binding it to the azelayl moiety, the compounds maintain biological activity. Compound 13 is still active against hematological cancer cell lines and shows a selective effect only on HT29 cells (IC50 = 0.006 µM) among solid tumor models. Compound 14 loses activity on all leukemic lines, while showing a high level of toxicity on all solid tumor lines tested (IC50 0.0015–0.469 µM).

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Hyperphosphorylation of CDH1 in Glioblastoma Cancer Stem Cells Attenuates APC/CCDH1 Activity and Pharmacologic Inhibition of APC/CCDH1/CDC20 Compromises Viability

Cited by 26 publications

References 57 publications

[Retracted] Potential Drug Prediction of Glioblastoma Based on Drug Perturbation‐Induced Gene Expression Signatures

[Retracted] Potential Drug Prediction of Glioblastoma Based on Drug Perturbation‐Induced Gene Expression Signatures

ProTAME Arrest in Mammalian Oocytes and Embryos Does Not Require Spindle Assembly Checkpoint Activity

Synthesis of Novel Tryptamine Derivatives and Their Biological Activity as Antitumor Agents

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