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Research Paper|Volume 12, Issue 10|pp 9475—9488

Amphiregulin promotes cisplatin chemoresistance by upregulating ABCB1 expression in human chondrosarcoma

Yu-Wen Huang1, Chih-Yang Lin2, Hsiao-Chi Tsai3, Yi-Chin Fong4,5, Chien-Kuo Han6, Yuan-Li Huang6, Wen-Tung Wu7, Shih-Ping Cheng2,3,8, Hao-Chiun Chang9,10, Kuang-Wen Liao10,11, Shih-Wei Wang2,12, Chih-Hsin Tang1,6,12,13,14
  • 1Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
  • 2Department of Medicine, Mackay Medical College, New Taipei, Taiwan
  • 3Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
  • 4Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
  • 5Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
  • 6Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
  • 7Department of Food Science and Nutrition, Meiho University, Pingtung, Taiwan
  • 8Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan
  • 9Department of Orthopaedics, MacKey Memorial Hospital, Taipei, Taiwan
  • 10Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
  • 11Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
  • 12Ph.D. Degree Program of Biomedical Science and Engineering, National Chiao Tung University, Hsinchu City, Taiwan
  • 13Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu, Taiwan
  • 14Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
* Equal contribution
Received: February 1, 2020Accepted: March 31, 2020Published: May 19, 2020
https://doi.org/10.18632/aging.103220

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.