软骨肉瘤是第二常见的骨癌类型。目前，临床上最有效的治疗方法是手术切除。顺铂是最广泛用于治疗软骨肉瘤的化疗药物；然而，其有效性受到耐药性的严重阻碍。在当前的研究中，我们通过RNA测序将顺铂耐药的软骨肉瘤SW1353细胞与其亲本细胞进行了比较。我们的分析表明，谷氨酰胺代谢在耐药细胞中高度激活，但葡萄糖代谢则不然。双调蛋白 (AR) 是表皮生长因子受体的配体，通过促进 NADPH 产生和抑制活性氧 (ROS) 积累，增强谷氨酰胺代谢并支持人软骨肉瘤的顺铂耐药性。 MEK、ERK 和 NrF2 信号通路可调节顺铂耐药软骨肉瘤中 AR 介导的丙氨酸-丝氨酸-半胱氨酸转运蛋白 2 (ASCT2；也称为 SLC1A5) 和谷氨酰胺酶 (GLS) 表达以及谷氨酰胺代谢。顺铂耐药软骨肉瘤细胞中 AR 表达的敲低可降低体内 SLC1A5 和 GLS 的表达。这些结果表明，AR 和谷氨酰胺代谢值得作为治疗顺铂耐药的人软骨肉瘤的治疗靶标。© 作者。

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.© The author(s).