乳酸介导的GPR81激活调节了慢性髓性白血病细胞的BCR/Abl蛋白表达,这些细胞是在低氧张力下选择的
Giulio Menegazzi1, Dayana Desideri1, Alessio Biagioni1
1Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, Florence, Italy.
The Journal of pathology
|October 23, 2025
概括
细胞外乳酸通过GPR81受体抑制慢性髓性白血病 (CML) 干细胞中的BCR/Abl蛋白,影响氨酸激酶抑制剂 (TKI) 耐药性. 了解这种机制对于开发新的CML疗法至关重要.
科学领域:
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
- 生物化学 生化学
背景情况:
- 慢性髓性白血病 (CML) 是由BCR/Abl氨酸激酶 (TK) 驱动的.
- 低氧干细胞 (SCN) 中的白血病干细胞 (LSC) 抑制BCR/Abl,从而对TK抑制剂 (TKI) 产生抗性.
- 以前的工作将BCR/Abl抑制与培养中的葡萄糖耗尽联系在一起.
研究的目的:
- 研究葡萄糖代谢的副产品乳酸在调节BCR/Abl蛋白表达中的作用.
- 阐明乳酸通过哪种信号途径影响CML干细胞中的BCR/Abl水平.
- 确定克服CML中TKI耐药性的潜在治疗点.
主要方法:
- 用糖解抑制剂 (2-DG) 和单碳酸转运体 (MCT) 抑制剂治疗CML细胞.
- 实验涉及操纵细胞外乳酸水平和使用GPR81受体激活剂和对抗剂.
- 在不同的代谢条件下评估了BCR/Abl蛋白表达和干细胞表型.
主要成果:
- 抑制糖解或乳酸分泌增加了BCR/Abl蛋白表达.
- 外源乳酸添加抑制了BCR/Abl表达,这种效应被GPR81对抗逆转.
- 通过乳酸激活GPR81,在低氧环境中抑制BCR/Abl.
结论:
- 细胞外乳酸通过GPR81受体起作用,在低氧条件下抑制CML细胞中的BCR/Abl蛋白表达.
- 这种乳酸中介抑制有助于TKI抵抗白血病干细胞.
- 向乳酸-GPR81轴可能为针对TCI耐药性CML提供新的治疗策略.
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