文章：

GW0742作为潜在的TRα和TRβ拮抗剂，可降低成人颗粒细胞瘤细胞系的存活率和代谢活性，并同时上调TRβ表达。

GW0742 as a Potential TRα and TRβ Antagonist Reduces the Viability and Metabolic Activity of an Adult Granulosa Tumour Cell Line and Simultaneously Upregulates TRβ Expression

原文发布日期：5 December 2024

DOI: 10.3390/cancers16234069

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Clinical studies have demonstrated a correlation between alterations in the expression level of TRα and TRβ receptors in ovarian cancer cells and overall survival. Celecoxib and GW0742, commonly known as a COX-2 inhibitor and a PPARβ/δ agonist, are novel thyroid hormone receptor antagonists that bind to TRβ or both TRα and TRβ. Methods: The study was conducted on a non-luteinized ovarian granulosa cell line (HGrC1) and two rare ovarian cancer cell lines (COV434 and KGN). The expression of TRα and TRβ at the gene and protein levels was examined by real-time PCR and Western blot, respectively. The impact of GW0742 and celecoxib on the cell viability of the HGrC1, COV434 and KGN lines was evaluated using the PrestoBlue™ Cell Viability Reagent. The metabolic activity of the cells was analysed using the Seahorse XFp Analyzer. Results: Initially, we observed that the gene and protein expression levels of TRα and TRβ were higher in COV434 and KGN cells than in HGrC1 cells. Subsequently, it was demonstrated that T3enhances the viability of HGrC1, COV434 and KGN cells. Furthermore, autoregulatory feedback loops were not observed during TRα or TRβ signalling in ovarian cancer cells, in contrast to the findings in healthy granulosa cells. Finally, we demonstrated that GW0742 reduced the viability and metabolic activity of granulosa cell tumours (GCTs). Simultaneously, we observed that GW0742 upregulated the expression of TRβ in GCT. Conclusions: These findings suggest that GW0742 may be a novel adjuvant therapy for GCTs expressing TRα and TRβ.

摘要翻译： 

背景/目的：临床研究表明，卵巢癌细胞中TRα和TRβ受体表达水平的改变与患者总生存期存在相关性。塞来昔布和GW0742分别作为COX-2抑制剂和PPARβ/δ激动剂，是新型甲状腺激素受体拮抗剂，可特异性结合TRβ或同时作用于TRα与TRβ。方法：本研究采用非黄素化卵巢颗粒细胞系（HGrC1）及两种罕见卵巢癌细胞系（COV434和KGN）。通过实时荧光定量PCR和蛋白质印迹法分别检测TRα和TRβ在基因及蛋白水平的表达。使用PrestoBlue™细胞活性检测试剂评估GW0742和塞来昔布对HGrC1、COV434及KGN细胞系活力的影响，并采用Seahorse XFp分析仪检测细胞代谢活性。结果：首先观察到COV434和KGN细胞中TRα和TRβ的基因及蛋白表达水平均高于HGrC1细胞。随后证实T3能增强HGrC1、COV434和KGN细胞的活力。此外，与健康颗粒细胞不同，卵巢癌细胞中TRα或TRβ信号通路未观察到自我调节反馈回路。最后，研究发现GW0742能降低颗粒细胞瘤（GCTs）的细胞活力与代谢活性，同时上调GCTs中TRβ的表达。结论：这些发现表明，GW0742可能成为表达TRα和TRβ的颗粒细胞瘤的新型辅助治疗药物。

原文链接：

GW0742 as a Potential TRα and TRβ Antagonist Reduces the Viability and Metabolic Activity of an Adult Granulosa Tumour Cell Line and Simultaneously Upregulates TRβ Expression