Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis
Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis
复制标题
抑制 AXL 通过减少糖酵解增强人卵巢癌细胞对顺铂的化学敏感性
DOI：
10.1038/s41401-020-00546-8
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发表时间：
2020-11-04
影响因子：
8.2
通讯作者：
Cheng, Yan
中科院分区：
文献类型：
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作者：
Tian, Min;Chen, Xi-sha;Cheng, Yan
Anexelekto （AXL）是TYRO3-AXL-MER （TAM）受体酪氨酸激酶（RTK）家族的一员，在多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和蛋白在OvCa组织中的表达明显高于正常卵巢上皮组织。在人OvCa细胞系中，抑制AXL可显著抑制细胞增殖，增加OvCa细胞对顺铂的敏感性，裸鼠成瘤实验也证实了这一点。KEGG分析显示AXL在肿瘤糖酵解通路中显著富集。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在Y105位点磷酸化丙酮酸激酶（PKM2）的M2异构体介导的。与亲代A2780细胞相比，顺铂耐药OvCa细胞A2780/DDP中AXL的表达显著升高。抑制AXL可降低A2780/DDP细胞的糖酵解水平，增加顺铂对A2780/DDP细胞的细胞毒性，提示AXL介导的糖酵解与OvCa的顺铂耐药有关。综上所述，本研究首次证明了AXL参与了Warburg效应的调控。我们的研究结果不仅突出了靶向AXL的临床价值，也为AXL抑制剂与顺铂联合治疗OvCa提供了理论依据。
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.