Research Paper Volume 12, Issue 10 pp 9475—9488
Amphiregulin promotes cisplatin chemoresistance by upregulating ABCB1 expression in human chondrosarcoma
- 1 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- 2 Department of Medicine, Mackay Medical College, New Taipei, Taiwan
- 3 Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
- 4 Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
- 5 Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
- 6 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
- 7 Department of Food Science and Nutrition, Meiho University, Pingtung, Taiwan
- 8 Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan
- 9 Department of Orthopaedics, MacKey Memorial Hospital, Taipei, Taiwan
- 10 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
- 11 Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- 12 Ph.D. Degree Program of Biomedical Science and Engineering, National Chiao Tung University, Hsinchu City, Taiwan
- 13 Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan
- 14 Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
Received: February 1, 2020 Accepted: March 31, 2020 Published: May 19, 2020
https://doi.org/10.18632/aging.103220How to Cite
Copyright © 2020 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
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.