Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
Aging (Albany NY). 2020 May 19;12(10):9475-9488. doi: 10.18632/aging.103220.
Chondrosarcomas are well known for their resistance to chemotherapeutic agents, including cisplatin, which is commonly used in chondrosarcomas. Amphiregulin (AR), a ligand of epidermal growth factor receptor (EGFR), plays an important role in drug resistance. We therefore sought to determine the role of AR in cisplatin chemoresistance. We found that AR inhibits cisplatin-induced cell apoptosis and promotes ATP-binding cassette subfamily B member 1 (ABCB1) expression, while knockdown of ABCB1 by small interfering RNA (siRNA) reverses these effects. High phosphoinositide 3-kinase (PI3K), Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation levels were observed in cisplatin-resistant cells. Pretreating chondrosarcoma cells with PI3K, Akt and NF-κB inhibitors or transfecting the cells with p85, Akt and p65 siRNAs potentiated cisplatin-induced cytotoxicity. In a mouse xenograft model, knockdown of AR expression in chondrosarcoma cells increased the cytotoxic effects of cisplatin and also decreased tumor volume and weight. These results indicate that AR upregulates ABCB1 expression through the PI3K/Akt/NF-κB signaling pathway and thus contributes to cisplatin resistance in chondrosarcoma.
软骨肉瘤对包括顺铂在内的化疗药物具有很强的耐药性，顺铂常用于软骨肉瘤的治疗。表皮生长因子受体 (EGFR) 的配体 Amphiregulin (AR) 在耐药性中发挥重要作用。因此，我们试图确定 AR 在顺铂耐药性中的作用。我们发现 AR 抑制顺铂诱导的细胞凋亡，并促进 ATP 结合盒亚家族 B 成员 1 (ABCB1) 的表达，而用小干扰 RNA (siRNA) 敲低 ABCB1 则逆转了这些作用。在耐药细胞中观察到高磷酸肌醇 3-激酶 (PI3K)、Akt 和核因子 kappa-轻链增强子的活化 B 细胞 (NF-κB) 磷酸化水平。用 PI3K、Akt 和 NF-κB 抑制剂预处理软骨肉瘤细胞，或用 p85、Akt 和 p65 siRNA 转染细胞，均可增强顺铂诱导的细胞毒性。在小鼠异种移植模型中，软骨肉瘤细胞中 AR 表达的敲低增加了顺铂的细胞毒性，同时也降低了肿瘤体积和重量。这些结果表明，AR 通过 PI3K/Akt/NF-κB 信号通路上调 ABCB1 的表达，从而导致软骨肉瘤对顺铂耐药。
