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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.

Citation

Yu-Wen Huang, Chih-Yang Lin, Hsiao-Chi Tsai, Yi-Chin Fong, Chien-Kuo Han, Yuan-Li Huang, Wen-Tung Wu, Shih-Ping Cheng, Hao-Chiun Chang, Kuang-Wen Liao, Shih-Wei Wang, Chih-Hsin Tang. Amphiregulin promotes cisplatin chemoresistance by upregulating ABCB1 expression in human chondrosarcoma. Aging. 2020 May 19;12(10):9475-9488

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PMID: 32428872

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