Inhibition of AXL enhances chemosensitivity of human ovarian cancer cells to cisplatin via decreasing glycolysis

Min Tian1,2, Xi-sha Chen1, Lan-ya Li1,2, Hai-zhou Wu1,2, Da Zeng3, Xin-luan Wang4, Yi Zhang5, Song-shu Xiao3, Yan Cheng1
1 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China
2 Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410008, China
3 Department of Gynecology and Obstetrics, The Third Xiangya Hospital, Central South University, Changsha 410008, China
4 Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518057, China
5 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou 215000, China
Correspondence to: Song-shu Xiao:, Yan Cheng:,
DOI: 10.1038/s41401-020-00546-8
Received: 13 February 2020
Accepted: 21 September 2020
Advance online: 4 November 2020


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.
Keywords: ovarian neoplasms; AXL; R428; tumor metabolism; Warburg effect; glycolysis; PKM2; cisplatin resistance

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