Journal of Otolaryngology and Ophthalmology of Shandong University ›› 2020, Vol. 34 ›› Issue (4): 105-110.doi: 10.6040/j.issn.1673-3770.0.2019.503

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Cisplatin resistance in nasopharyngeal carcinoma cells is affected by Notch receptors through the regulation of epithelial-mesenchymal transition rather than cell cycle controlHAN Jibo, ZOU You, YANG Rui, TAO Zezhang Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, ChinaAbstract:Objective〓

The objective of this study was to analyze the effects and possible regulatory mechanisms that Notch receptors could have on cisplatin resistance, observed in nasopharyngeal carcinoma. MethodsWestern blot analysis was used for the detection of Notch receptor expression in nasopharyngeal carcinoma cells and cisplatin-resistant nasopharyngeal carcinoma cells(5-8F, 5-8F/CDDP). Flow cytometry was used to investigate how the combined treatment with 10 μM CDDP and different concentrations of γ-secretase inhibitor(DAPT)could affect apoptosis in 5-8F/CDDP cells. Flow cytometry was also used for the detection of cell cycle stages in DAPT-treated 5-8F / CDDP cells. Finally, western blotting was also used for the detection of drug resistance-related protein expression. All experiments were followed by statistical data analysis. ResultsWe observed significantly higher Notch1 and Notch4 receptor expression in 5-8F/CDDP cells than in 5-8F cells(P=0.003, P=0.004). Furthermore, we described that Notch signaling was inhibited by DAPT in 5-8F/CDDP cells, followed by a significant increase in the apoptosis rate and decrease in cell proliferation, induced by cisplatin in a dose-dependent manner(P<0.05). Moreover, after inhibiting the Notch signaling pathway in 5-8F/CDDP cells, DAPT treatment significantly decreased the expression of Cyclin E and CDK-2, proteins involved in cell cycle regulation, and contributed to blocking the cells in the G1/S phase(P<0.05). At the same time, the expression levels of both the EMT-related protein Slug and the DNA excision repair protein ERCC1 significantly decreased, while that of E-Cadherin was up-regulated. ConclusionUp-regulated expression of Notch1 and Notch4 receptors is associated with cisplatin resistance in nasopharyngeal carcinoma cells. The inactivation of the Notch signaling pathway might thus have the potential to enhance the efficiency of cisplatin chemotherapy in drug-resistant nasopharyngeal carcinoma cells by inhibiting EMT rather than blocking the G1/S cell cycle phase.