Blocking Mitotic Exit of Ovarian Cancer Cells by Pharmaceutical Inhibition of the Anaphase-Promoting Complex Reduces Chromosomal Instability

Raab, Monika; Sanhaji, Mourad; Zhou, Shengtao; Rödel, Franz; El‐Balat, Ahmed; Becker, Sven; Strebhardt, Klaus

doi:10.1016/j.neo.2019.01.007

Cited by 30 publications

(31 citation statements)

References 67 publications

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“…In addition, although it has not been completedly translated to clinical trials, a specific PLK1 inhibitor, onvansertib, has shown good tolerance and efficacy in combination therapy with decitabine for leukemia treatment [31]. High expression of PLK1 has been reported to link to poor prognosis in patients, and targeting inhibition of PLK1 in combination with paclitaxel and proTAME has shown potent effects on the reduction of chromosomal instability and the subsequent apoptosis of OC cells [32]. These results indicated that miR-545-mediated PLK1 downregulation has potentials in OC control.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation

Zhang

et al. 2021

BMC Cancer

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Background Ovarian cancer (OC) is a life-threatening gynecological malignancy where dysregulation of microRNAs (miRNAs) is frequently implicated. This study focuses on the function of miR-545 on OC development and the molecules involved. Methods miR-545 expression in OC tissues and cell lines was determined, and its link to the survival of patients was analyzed. Altered expression of miR-545 was induced to determine its role in proliferation, apoptosis, migration and invasion of OC cells and the angiogenesis ability of human umbilical vein endothelial cells (HUVECs). The targeting mRNAs of miR-545 were predicted and validated through luciferase assays. Gain-of-function studies of KDM4B and PLK1 were performed to explore their involvements in OC development. In vivo experiments were conducted by inducing xenograft tumors in nude mice. Results Poor expression of miR-545 was found in OC tissues and cells compared to the normal ones and it indicated unfavorable prognosis in patients. Overexpression of miR-545 suppressed growth, migration, invasion and angiogenesis of OC cells as well as the angiogenesis ability of HUVECs. miR-545 was found to target mRNAs of KDM4B and PLK1, while KDM4B promoted the transcription of the PLK1 promoter through demethylation of H3K9me3. Either overexpression of KDM4B or PLK1 partially blocked the inhibitory effects of miR-545 mimic on OC cell growth, especially the former one. The in vitro results were reproduced in vivo. Conclusion This study evidenced that miR-545 suppresses progression of OC through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation

Zhang

et al. 2021

BMC Cancer

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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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“…"Sustaining proliferative signaling" is a hallmark in cancer, but it might play a more dominant role in early-stages of OC than in late stages, where "activation of invasion/metastasis" or "resistance to cell death" take over in the overall clinical picture of OC. In the light of those thoughts, Ki-67 and Plk1 as targets for OC (55)(56)(57) come in consideration for early-stage OC in addition to their roles as diagnostic markers. Ki-67 is currently being tested in preclinical trials and small molecule inhibitors of Plk1 have received break-through designation by the FDA for clinical trials.…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Relevance of the Proliferation Markers Ki-67 and Plk1 in Early-Stage Ovarian Cancer Patients With Serous, Low-Grade Carcinoma Based on mRNA and Protein Expression

et al. 2020

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Since type and duration of an appropriate adjuvant chemotherapy in early-stage ovarian cancer (OC) are still being debated, novel markers for a better stratification of these patients are of utmost importance for the design of an improved chemotherapeutical strategy. In contrast to numerous cancer studies on cellular proliferation based on the immunohistochemistry-driven evaluation of protein expression, we compared mRNA and protein expression of two independent markers of cellular proliferation, Ki-67 and Plk1, in a large cohort of 243 early-stage OC and their relationship with clinicopathological features and survival. Based on marker expression we demonstrate that early-stage OC patients (stages I/II, low-grade, serous) with high expression (Ki-67, Plk1) had a significantly shorter progression-free survival (PFS) and overall survival (OS) compared to patients with low expression (Ki-67, Plk1). Remarkably, based on mRNA expression this significant difference got lost in advanced stages (III/IV): At least for PFS, high levels of Ki-67 and Plk1 correlate with moderately better survival compared to patients with low expressing tumors. Our data suggest that in addition to Ki-67, Plk1 is a novel marker for the stratification of early-stage OC patients to maximize therapeutic efforts. Both, Ki-67 and Plk1, seem to be better suited in early-stages (I/II) as therapeutical targets compared to advanced-stages (III/IV) OC.

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Blocking Mitotic Exit of Ovarian Cancer Cells by Pharmaceutical Inhibition of the Anaphase-Promoting Complex Reduces Chromosomal Instability

Cited by 30 publications

References 67 publications

MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation

MicroRNA-545 suppresses progression of ovarian cancer through mediating PLK1 expression by a direct binding and an indirect regulation involving KDM4B-mediated demethylation

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

The Prognostic Relevance of the Proliferation Markers Ki-67 and Plk1 in Early-Stage Ovarian Cancer Patients With Serous, Low-Grade Carcinoma Based on mRNA and Protein Expression

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