Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20

Richeson, Katherine; Bodrug, Tatyana; Sackton, Katharine; Yamaguchi, Masaya; Paulo, João A.; Gygi, Steven P.; Schulman, Brenda A.; Brown, Nicholas G.; King, Randall W.

doi:10.1038/s41589-020-0495-z

Cited by 24 publications

(23 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[24][25][26] CDC20 is a vital conserved cell cycle regulator that modulates ubiquitin ligase activity of the APC/C complex at the moment of the metaphase-anaphase transition in mitosis and degrades the substrates of APC/C CDC20 including securin and cyclin A. 27,28 Previous researches have revealed that CDC20 suppressed apoptosis while accelerated the proliferation and invasion of osteosarcoma cells. 29,30 Cyclin A2, as part of the substrates of APC/C CDC20 , is tightly linked with the process of sister chromatid segregation.…”

Section: Dovepressmentioning

confidence: 99%

NUSAP1 Accelerates Osteosarcoma Cell Proliferation and Cell Cycle Progression via Upregulating CDC20 and Cyclin A2

Wang¹,

Liu²,

Wu³

et al. 2021

OTT

View full text Add to dashboard Cite

Purpose: Nucleolar and spindle-associated protein 1 (NUSAP1) is a significant mitotic regulator and has been found to be implicated in carcinogenesis of several cancers. The aim of this study was to explore the functional role and underlying mechanisms of NUSAP1 in osteosarcoma. Methods: Western blot assay and Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) were employed to assess the expressions of NUSAP1, cell division cycle 20 homologue (CDC20) and cyclin A2 (CCNA2) in osteosarcoma cells. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2′-deoxyuridine (EdU) assay, and flow cytometry was applied for exploring cell cycle. In addition, an osteosarcoma tumor-bearing mouse model was established by injection of transfected osteosarcoma cells. Tumor volume and protein expressions of Ki67 and PCNA were examined. Bioinformatics analysis and immunoprecipitation were used to identify the combination of NUSAP1 with CDC20 and CCNA2. Results: The mRNA and protein expression of NUSAP1 were extremely upregulated in osteosarcoma cells. Overexpression of NUSAP1 promoted whereas NUSAP1 silencing suppressed cell proliferation and cell cycle progression in transfected osteosarcoma cells. In osteosarcoma mouse model, NUSAP1 expression affected tumor volume and levels of Ki67 and PCNA. Moreover, CDC20 or CCNA2 silencing inhibited NUSAP1-induced cell proliferation and cell cycle in osteosarcoma cells. Conclusion:Our data demonstrated that upregulated NUSAP1 may exacerbate the development of osteosarcoma by accelerating the proliferation and cell cycle process of osteosarcoma cells by binding to CDC20 and CCNA2, suggesting NUSAP1 as a possible therapeutic target for treatment of osteosarcoma.

show abstract

Section: Dovepressmentioning

confidence: 99%

NUSAP1 Accelerates Osteosarcoma Cell Proliferation and Cell Cycle Progression via Upregulating CDC20 and Cyclin A2

Wang¹,

Liu²,

Wu³

et al. 2021

OTT

View full text Add to dashboard Cite

show abstract

“…Second, it would be necessary to perform an experiment to show, for example, that the same over expressed peptide derived from Cdc20 from between the ‘C-box’ and the ‘Mad2-binding motif’ or ‘KILR motif’ does not affect MCC function by observing under the light microscope if any cells escape from a benomyl arrest when the peptide is expressed. This experiment is required because of the unexpected result displayed by apcin, where it displayed great promise as an APC/C Cdc20 -specific inhibitor, but, unfortunately, also disrupts the function of the MCC, thus allowing cancer cells to still execute ‘mitotic slippage’ by entering anaphase, even in the presence of a mitotic poison [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, the current only known essential function of the APC/C Cdc20 form of the holoenzyme in humans is the promotion of somatic cell mitotic cell division, or it is also likely to be involved in the promotion of the metaphase II–anaphase II advance during meiosis II in gametogenesis, as in mice [ 23 ]. Surprisingly, even the most promising APC/C Cdc20 inhibitor molecule apcin gave an unexpected result, namely, in the absence of mitotic poisons, it induced the expected cell cycle arrest at metaphase, but in the presence of mitotic poisons, which would be the expected conditions in cancer cells in individuals undergoing chemotherapy, apcin induced ‘mitotic slippage’, rather than preventing it, by not only decreasing APC/C Cdc20 activity, but also by blocking mitotic checkpoint MCC function, the opposite of the desired result [ 24 ]. Thus, the goal to identify a specific APC/C Cdc20 inhibitor that can extend a mitotic poison induced spindle checkpoint arrest remains unfulfilled.…”

Section: Introductionmentioning

confidence: 99%

Using Budding Yeast to Identify Molecules That Block Cancer Cell ‘Mitotic Slippage’ Only in the Presence of Mitotic Poisons

Schuyler

Chen

2021

IJMS

View full text Add to dashboard Cite

Research on the budding yeast Saccharomyces cerevisiae has yielded fundamental discoveries on highly conserved biological pathways and yeast remains the best-studied eukaryotic cell in the world. Studies on the mitotic cell cycle and the discovery of cell cycle checkpoints in budding yeast has led to a detailed, although incomplete, understanding of eukaryotic cell cycle progression. In multicellular eukaryotic organisms, uncontrolled aberrant cell division is the defining feature of cancer. Some of the most successful classes of anti-cancer chemotherapeutic agents are mitotic poisons. Mitotic poisons are thought to function by inducing a mitotic spindle checkpoint-dependent cell cycle arrest, via the assembly of the highly conserved mitotic checkpoint complex (MCC), leading to apoptosis. Even in the presence of mitotic poisons, some cancer cells continue cell division via ‘mitotic slippage’, which may correlate with a cancer becoming refractory to mitotic poison chemotherapeutic treatments. In this review, knowledge about budding yeast cell cycle control is explored to suggest novel potential drug targets, namely, specific regions in the highly conserved anaphase-promoting complex/cyclosome (APC/C) subunits Apc1 and/or Apc5, and in a specific N-terminal region in the APC/C co-factor cell division cycle 20 (Cdc20), which may yield molecules which block ‘mitotic slippage’ only in the presence of mitotic poisons.

show abstract

“…CDC20, which was key to chromosome segregation and mitosis exit, plays an important role in cell cycle progressing [43]. It can activate a ligase, the anaphase-promoting complex/cyclosome (APC/C), which starts the anaphase and mitotic exit [44]. Cheng et al shown that overexpression of CDC20 promotes the metastasizing of breast cancer [45].…”

Section: Discussionmentioning

confidence: 99%

Selected Ideal Natural Ligand Against TNBC by Inhibiting CDC20, Using Bioinformatics and Molecular Biology

Liu

Wang

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Triple-negative breast cancer (TNBC), as the most aggressive kinds of breast tumor, still cannot get effective targeted therapy. Recently, techniques of bioinformatics and molecular biology were hot topics in drug development. We want to find potential therapeutic targets of triple-negative breast cancer (TNBC) patients by bioinformatics and screen ideal natural ligand that can bind with the potential target and inhibit it by using molecular biology.Methods: Bioinformatics and molecular biology were combined to analyze potential therapeutic targets. Differential expression analysis identified the differentially expressed genes (DEGs) between TNBC tissues and normal tissues. The functional enrichment analyses of DEGs shown the important gene ontology (GO) terms and pathways of TNBC. Protein-protein interaction (PPI) network construction screened 20 hub genes, while Kaplan website was used to analyze the relationship between the survival curve and expression of hub genes. Then Discovery Studio 4.5 screened ideal natural inhibitors of the potential therapeutic target by LibDock, ADME, toxicity prediction, CDOCKER and molecular dynamic simulation.Results: 1,212 and 353 DEGs were respectively found between TNBC tissues and normal tissues, including 88 up-regulated and 141 down-regulated DEGs in both databases. 20 hub genes were screened, and the higher expression of CDC20 was associated with a poor prognosis. Therefore, we chose CDC20 as the potential therapeutic target. 7,416 natural ligands were conducted to bind firmly with CDC20, and among these ligands, ZINC000004098930 was regarded as the potential ideal ligand, owing to its non-hepatotoxicity, more solubility level and less carcinogenicity than the reference drug, apcin. The ZINC000004098930-CDC20 could exist stably in natural environment.Conclusion: 20 genes were regarded as hub genes of TNBC and most of them were relevant to the survival curve of breast cancer patients, especially CDC20. ZINC000004098930 was chosen as the ideal natural ligand that can targeted and inhibited CDC20, which may give great contribution to TNBC targeted treatment.

show abstract

Paradoxical mitotic exit induced by a small molecule inhibitor of APC/CCdc20

Cited by 24 publications

References 57 publications

NUSAP1 Accelerates Osteosarcoma Cell Proliferation and Cell Cycle Progression via Upregulating CDC20 and Cyclin A2

NUSAP1 Accelerates Osteosarcoma Cell Proliferation and Cell Cycle Progression via Upregulating CDC20 and Cyclin A2

Using Budding Yeast to Identify Molecules That Block Cancer Cell ‘Mitotic Slippage’ Only in the Presence of Mitotic Poisons

Selected Ideal Natural Ligand Against TNBC by Inhibiting CDC20, Using Bioinformatics and Molecular Biology

Contact Info

Product

Resources

About