Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008, China.
Acta Pharmacol Sin. 2021 Jul;42(7):1180-1189. doi: 10.1038/s41401-020-00546-8. Epub 2020 Nov 4.
Anexelekto (AXL), a member of the TYRO3-AXL-MER (TAM) family of receptor tyrosine kinases (RTK), is overexpressed in varieties of tumor tissues and promotes tumor development by regulating cell proliferation, migration and invasion. In this study, we investigated the role of AXL in regulating glycolysis in human ovarian cancer (OvCa) cells. We showed that the expression of AXL mRNA and protein was significantly higher in OvCa tissue than that in normal ovarian epithelial tissue. In human OvCa cell lines suppression of AXL significantly inhibited cell proliferation, and increased the sensitivity of OvCa cells to cisplatin, which also proved by nude mice tumor formation experiment. KEGG analysis showed that AXL was significantly enriched in the glycolysis pathways of cancer. Changes in AXL expression in OvCa cells affect tumor glycolysis. We demonstrated that the promotion effect of AXL on glycolysis was mediated by phosphorylating the M2 isoform of pyruvate kinase (PKM2) at Y105. AXL expression was significantly higher in cisplatin-resistant OvCa cells A2780/DDP compared with the parental A2780 cells. Inhibition of AXL decreased the level of glycolysis in A2780/DDP cells, and increased the cytotoxicity of cisplatin against A2780/DDP cells, suggesting that AXL-mediated glycolysis was associated with cisplatin resistance in OvCa. In conclusion, this study demonstrates for the first time that AXL is involved in the regulation of the Warburg effect. Our results not only highlight the clinical value of targeting AXL, but also provide theoretical basis for the combination of AXL inhibitor and cisplatin in the treatment of OvCa.
AXL（AXL）是酪氨酸激酶受体（RTK）TYRO3-AXL-MER（TAM）家族的成员，在各种肿瘤组织中过表达，并通过调节细胞增殖、迁移和侵袭来促进肿瘤的发展。在这项研究中，我们研究了 AXL 在调节人卵巢癌（OvCa）细胞糖酵解中的作用。我们发现 AXL mRNA 和蛋白的表达在 OvCa 组织中明显高于正常卵巢上皮组织。在人 OvCa 细胞系中，AXL 的抑制显著抑制了细胞增殖，并增加了 OvCa 细胞对顺铂的敏感性，这也通过裸鼠肿瘤形成实验得到了证明。KEGG 分析表明，AXL 在癌症的糖酵解途径中显著富集。OvCa 细胞中 AXL 表达的变化影响肿瘤糖酵解。我们证明了 AXL 对糖酵解的促进作用是通过使丙酮酸激酶（PKM2）的 M2 同工型 Y105 磷酸化来介导的。与亲本 A2780 细胞相比，顺铂耐药 OvCa 细胞 A2780/DDP 中 AXL 的表达明显更高。AXL 的抑制降低了 A2780/DDP 细胞中的糖酵解水平，并增加了顺铂对 A2780/DDP 细胞的细胞毒性，表明 AXL 介导的糖酵解与 OvCa 中的顺铂耐药有关。总之，这项研究首次证明 AXL 参与调节瓦伯格效应。我们的研究结果不仅突出了靶向 AXL 的临床价值，还为 AXL 抑制剂与顺铂联合治疗 OvCa 提供了理论基础。
