PPP和PI3K/AKT信号通路的反循环驱动HCC中的regorafenib耐药性
Huihua Yang1,2, Dahong Chen1, Yafei Wu1
1Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
肝细胞癌 (HCC) 中的雷戈拉费尼布耐药性与酸通路 (PPP) 有关. 针对PPP和PI3K/AKT的反循环可以克服HCC的这种药物耐药性.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生化学
背景情况:
- 肝细胞癌 (HCC) 的发病率和死亡率很高.
- 雷戈拉费尼布是晚期HCC的二线治疗,但耐药性是一个越来越大的挑战.
- 在HCC中形成对regorafenib耐药性的机制在很大程度上仍未被阐明.
研究的目的:
- 为了研究对regorafenib耐药HCC细胞的代谢概况.
- 为了确定参与regorafenib耐药性的关键代谢途径.
- 阐明对regorafenib耐药性的潜在分子机制.
主要方法:
- 代谢学被用来分析药物敏感和耐药的HCC细胞之间的代谢变化.
- 进行了细胞增殖,细胞亡和殖民地形成测试.
- 通过lentivirus进行葡萄糖-6-酸脱酶 (G6PD) 操纵和氧化应激标志物 (NADPH,ROS,GSH) 的评估.
主要成果:
- 酸途径 (PPP) 被确定为HCC对regorafenib耐药性的最相关的代谢途径.
- 抗雷戈拉费尼布的细胞表现出增加的G6PD活性和NADPH水平,与减少的氧化应激和亡相关.
- 抑制G6PD使耐药细胞敏感化,而过度表达敏感细胞则降低了regorafenib的疗效,表明G6PD的关键作用.
结论:
- 在PPP和PI3K/AKT信号通路之间的反循环驱动HCC中的regorafenib抵抗.
- 准这种PPP-PI3K/AKT反循环是克服HCC治疗中对regorafenib耐药性的潜在策略.
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