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TRPC5 mediates TMZ resistance in TMZ-resistant glioblastoma cells via NFATc3-P-gp pathway
Translational Oncology ( IF 5 ) Pub Date : 2021-09-06 , DOI: 10.1016/j.tranon.2021.101214
Yan Zou 1 , Zi'xiang Liu 1 , Yi'nan Zhou 1 , Jing Wang 1 , Qin'yi Xu 1 , Xu'dong Zhao 1 , Zeng'li Miao 1
Affiliation  

P-glycoprotein (P-gp) acts as a pump to transport cytotoxic drugs out of cells and is upregulated in cancer cells. Suppressing the expression of P-gp is an effective strategy to overcome multidrug resistance in cancer chemotherapy. Temozolomide (TMZ) is the recommended drug for the standard treatment of patients with glioblastoma, but its clinical application is restricted due to drug resistance. Transient receptor potential channel-5 (TRPC5), a Ca2+-permeable channel, has been attributed to a different drug resistance mechanism except DNA repair system; therefore, we aimed to elucidate the mechanism regarding the role of TRPC5 in TMZ resistance. TRPC5 and P-glycoprotein (P-gp) are upregulated in TMZ-resistant glioblastoma cell lines. The downregulation of TRPC5 inhibited P-gp expression and led to a significant reversal of TMZ resistance in TMZ-resistant cell lines. TRPC5-siRNA restricted the growth of tumour xenografts in an athymic nude mouse model of TMZ-resistant cells. In specimens from patients with recurrent glioblastoma, TRPC5 was found to be highly expressed, accompanied by the upregulation of P-gp expression. The nuclear factor of activated T cell isoform c3 (NFATc3), which acts as a transcriptional factor, bridges TRPC5 activity to P-gp induction. In conclusion, these results demonstrate the functional role of the TRPC5-NFATc3-P-gp signalling pathway in TMZ resistance in glioblastoma cells.



中文翻译:

TRPC5通过NFATc3-P-gp通路介导TMZ抗性胶质母细胞瘤细胞中的TMZ抗性

P-糖蛋白 (P-gp) 作为泵将细胞毒性药物转运出细胞,并在癌细胞中上调。抑制P-gp的表达是克服癌症化疗多药耐药的有效策略。替莫唑胺(TMZ)是胶质母细胞瘤患者标准治疗的推荐药物,但由于耐药性限制了其临床应用。瞬时受体电位通道 5 (TRPC5),一种 Ca 2+- 渗透性通道,已归因于除 DNA 修复系统之外的不同耐药机制;因此,我们旨在阐明 TRPC5 在 TMZ 抗性中的作用机制。TRPC5 和 P-糖蛋白 (P-gp) 在 TMZ 抗性胶质母细胞瘤细胞系中上调。TRPC5 的下调抑制了 P-gp 的表达,并导致 TMZ 抗性细胞系中 TMZ 抗性的显着逆转。TRPC5-siRNA 在 TMZ 抗性细胞的无胸腺裸鼠模型中限制肿瘤异种移植物的生长。在复发性胶质母细胞瘤患者的标本中,发现 TRPC5 高表达,伴随着 P-gp 表达的上调。激活的 T 细胞亚型 c3 (NFATc3) 的核因子作为转录因子,将 TRPC5 活性与 P-gp 诱导连接起来。综上所述,

更新日期:2021-09-07
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