WEE1 kinase inhibitor AZD1775 induces CDK1 kinase-dependent origin firing in unperturbed G1- and S-phase cells

Moiseeva, Tatiana N.; Qian, Chen’ao; Sugitani, Norie; Osmanbeyoglu, Hatice U.; Bakkenist, Christopher J.

doi:10.1073/pnas.1915108116

Cited by 67 publications

(85 citation statements)

References 19 publications

(35 reference statements)

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“…Complexes of cyclin-dependent kinases (CDKs) and cyclins the regulated cell cycle. CDK4/CDK6-cyclin D and CDK2-cyclin E separately altered the G1 and S phase of cells [ 31 ]. In our experiment, flow cytometry confirmed that EVI5L promoted S phase in GMECs, and the results of the WB assay for the protein of the cell cycle showed that EVI5L promoted the expression of CDK4, CDK2, cyclinD1 but inhibited cyclinE protein in GMECs.…”

Section: Discussionmentioning

confidence: 99%

CircRNA-006258 Sponge-Adsorbs miR-574-5p to Regulate Cell Growth and Milk Synthesis via EVI5L in Goat Mammary Epithelial Cells

Zhang

Liu

et al. 2020

Genes

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The development of the udder and the milk yield are closely related to the number and vitality of mammary epithelial cells. Many previous studies have proved that non-coding RNAs (ncRNAs) are widely involved in mammary gland development and the physiological activities of lactation. Our laboratory previous sequencing data revealed that miR-574-5p was differentially expressed during the colostrum and peak lactation stages, while the molecular mechanism of the regulatory effect of miR-574-5p on goat mammary epithelial cells (GMECs) is unclear. In this study, the targeting relationship was detected between miR-574-5p or ecotropic viral integration site 5-like (EVI5L) and circRNA-006258. The results declared that miR-574-5p induced the down-regulation of EVI5L expression at both the mRNA and protein levels, while circRNA-006258 relieved the inhibitory effect through adsorbing miR-574-5p. EVI5L blocked the G1 phase and promoted the S phase by activating the Rab23/ITGB1/TIAM1/Rac1-TGF-β/Smad pathway in GMECs. By increasing the protein expression of Bcl2 and reducing the protein expression of Bax, EVI5L promoted cell growth and inhibited apoptosis. The activation of the PI3K/AKT–mTOR signaling pathway promoted the production of triacylglycerol (TAG) and β-casein in GMECs. The circRNA–006258/miR-574-5p/EVI5L axis could regulate the cell growth and milk synthesis of GMECs by sponge-adsorbed miR-574-5p. These results would provide scientific evidence for precision animal breeding in the industry of dairy goats.

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Section: Discussionmentioning

confidence: 99%

CircRNA-006258 Sponge-Adsorbs miR-574-5p to Regulate Cell Growth and Milk Synthesis via EVI5L in Goat Mammary Epithelial Cells

Zhang

Liu

et al. 2020

Genes

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“…CDK1 (Cyclin-dependentkinase 1) is a serine/threonine-like protein kinase that plays an essential role in controlling cell proliferation at the G2/M point of the cell cycle. Some reports have con rmed that high CDK1 expression is an independent predictor for tumor recurrence in one and ve years, and it has been noted that compounds targeting CDK1 could be novel antitumor reagents [50][51][52] .…”

Section: Discussionmentioning

confidence: 99%

A Nomogram Based on Glycolysis-related Gene Expression Profilings Serve as a Novel Prognosis Risk Classifiers for Human Hepatocellular Carcinoma

Zhang

Dai

et al. 2021

Preprint

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Metabolic pattern reconstruction is an important element in tumor progression. The metabolism of tumor cells is characterized by the abnormal increase of anaerobic glycolysis, regardless of the higher oxygen concentration, resulting in a large accumulation of energy from glucose sources, and contributes to rapid cell proliferation and tumor growth which is further referenced as the Warburg effect. We tried to reconstruct the metabolic pattern in the progression of cancer to screen which genetic changes are specific in cancer cells. A total of 12 common types of solid tumors were enrolled in the prospective study. Gene set enrichment analysis (GSEA) was implemented to analyze 9 glycolysis-related gene sets, which are closely related to the glycolysis process. Univariate and multivariate analyses were used to identify independent prognostic variables for the construction of a nomogram based on clinicopathological characteristics and a glycolysis-related gene prognostic index (GRGPI). The prognostic model based on glycolysis genes has the highest area under the curve (AUC) in LIHC (Liver hepatocellular carcinoma). 8-gene signatures (AURKA, CDK1, CENPA, DEPDC1, HMMR, KIF20A, PFKFB4, STMN1) were related to overall survival (OS) and recurrence-free survival (RFS). Further analysis demonstrates that the prediction model can accurately distinguish between high- and low-risk cancer patients among patients in different clusters in LIHC. A nomogram with a well-fitted calibration curve based on gene expression profiles and clinical characteristics improves discrimination in internal and external cohorts. Furthermore, the altering expression of metabolic genes related to glycolysis may contribute to the reconstruction of the tumor-related microenvironment.

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“…Although different DDR inhibitors have partially overlapping effects, they have also unique and complementary modes of action, which are responsible for their synergy [ 68 , 70 , 72 , 84 , 85 , 86 ]. Thus, rational combinations of these inhibitors could be useful to overcome or prevent resistance [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the dl922-947 Oncolytic Virus in Malignant Mesothelioma Cell Lines

Iannuzzi

Indovina

Forte

et al. 2020

IJMS

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Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, for which no therapy proves to be effective. We have recently shown that the oncolytic adenovirus dl922-947 had antitumor effects in MM cell lines and murine xenografts. Previous studies demonstrated that dl922-947-induced host cell cycle checkpoint deregulation and consequent DNA lesions associated with the virus efficacy. However, the cellular DNA damage response (DDR) can counteract this virus action. Therefore, we assessed whether AZD1775, an inhibitor of the G2/M DNA damage checkpoint kinase WEE1, could enhance MM cell sensitivity to dl922-947. Through cell viability assays, we found that AZD1775 synergized with dl922-947 selectively in MM cell lines and increased dl922-947-induced cell death, which showed hallmarks of apoptosis (annexinV-positivity, caspase-dependency, BCL-XL decrease, chromatin condensation). Predictably, dl922-947 and/or AZD1775 activated the DDR, as indicated by increased levels of three main DDR players: phosphorylated histone H2AX (γ-H2AX), phospho-replication protein A (RPA)32, phospho-checkpoint kinase 1 (CHK1). Dl922-947 also increased inactive Tyr-15-phosphorylated cyclin-dependent kinase 1 (CDK1), a key WEE1 substrate, which is indicative of G2/M checkpoint activation. This increase in phospho-CDK1 was effectively suppressed by AZD1775, thus suggesting that this compound could, indeed, abrogate the dl922-947-induced DNA damage checkpoint in MM cells. Overall, our data suggest that the dl922-947-AZD1775 combination could be a feasible strategy against MM.

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WEE1 kinase inhibitor AZD1775 induces CDK1 kinase-dependent origin firing in unperturbed G1- and S-phase cells

Cited by 67 publications

References 19 publications

CircRNA-006258 Sponge-Adsorbs miR-574-5p to Regulate Cell Growth and Milk Synthesis via EVI5L in Goat Mammary Epithelial Cells

CircRNA-006258 Sponge-Adsorbs miR-574-5p to Regulate Cell Growth and Milk Synthesis via EVI5L in Goat Mammary Epithelial Cells

A Nomogram Based on Glycolysis-related Gene Expression Profilings Serve as a Novel Prognosis Risk Classifiers for Human Hepatocellular Carcinoma

Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the dl922-947 Oncolytic Virus in Malignant Mesothelioma Cell Lines

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