1. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
2. Department of Orthopedics, Chung Shan Medical University Hospital, Taichung, Taiwan.
3. Department of Orthopedics, Penghu Hospital, Ministry of Health and Welfare, Penghu, Taiwan.
4. School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
5. Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.
6. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
7. Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
8. Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
9. Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan.
10. Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.
11. Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
12. Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
13. Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan.
14. Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
15. Department of Medical Research, China Medical University Hsinchu Hospital, Hsinchu, Taiwan.
#These authors contributed equally to this work.
Chondrosarcoma is the second most common type of bone cancer. At present, the most effective clinical course of action is surgical resection. Cisplatin is the chemotherapeutic medication most widely used for the treatment of chondrosarcoma; however, its effectiveness is severely hampered by drug resistance. In the current study, we compared cisplatin-resistant chondrosarcoma SW1353 cells with their parental cells via RNA sequencing. Our analysis revealed that glutamine metabolism is highly activated in resistant cells but glucose metabolism is not. Amphiregulin (AR), a ligand of the epidermal growth factor receptor, enhances glutamine metabolism and supports cisplatin resistance in human chondrosarcoma by promoting NADPH production and inhibiting reactive oxygen species (ROS) accumulation. The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.
Keywords: chondrosarcoma, amphiregulin, SLC1A5, GLS, cisplatin