[No authors listed]
Acquired resistance to cisplatin (CDDP) in esophageal squamous cell carcinoma (ESCC) remains a major challenge in cancer therapy. Although progress has been made in identifying the mechanisms responsible for resistance to CDDP, the underlying mechanisms of resistance in ESCC are still not entirely understood. In the present study, a CDDPâresistant ESCC cell line EC109/CDDP was established by culturing parental EC109 cells in increasing concentrations of CDDP, and it was demonstrated that MutY homolog (MUTYH), a critical base excision repair gene, was significantly downregulated in the resistant EC109/CDDP cells compared with that noted in the parental cells. Ectopic expression of MUTYH by transient transfection of pcDNA3.1âMUTYH plasmid significantly enhanced the CDDPâmediated inhibitory effect on resistant cell proliferation and induction of apoptosis, while silencing of MUTYH by transiently transfecting MUTYHâtargeted siRNA in parental cells led to decreased sensitivity to CDDP as demonstrated by MTT assay, suggesting the crucial involvement of MUTYH in CDDP resistance. Further experiments demonstrated that the CDDPâresistant cells went through epithelialâmesenchymal transition (EMT) driven by its master regulator Twist, and MUTYH overexpression significantly reduced the Twist expression level and reversed the phenotype of EMT as detected by western blot analysis and RTâqPCR assays, suggesting that downregulation of MUTYH contributed to the Twistâmediated EMT. Moreover, it was observed that the effect of MUTYH on Twist was also associated with its degradation in addition to transcription. MUTYH acted as a positive regulator of reactive oxygen species that showed a low level in resistant cells via ï¬ow cytometry assay, as demonstrated by increased production in response to MUTYH overexpression. Reduced duanyu1670 by using Nâacetylcysteine led to a decrease in proteasome activity and sequentially inhibited the degradation of Twist. In conclusion, the present data demonstrated that EMT activation mediated by MUTYH downregulation, by both enhancing Twist transcription and blocking its degradation, is one of the mechanisms for acquisition of CDDP resistance in ESCC.
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