Propofol inhibits biological functions of leukaemia stem and differentiated cells through suppressing Wnt/β-catenin and Akt/mTOR
Propofol inhibits biological functions of leukaemia stem and differentiated cells through suppressing Wnt/β-catenin and Akt/mTOR
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DOI：
10.1111/1440-1681.13167
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发表时间：
2019-09-17
影响因子：
2.9
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Chen, Liufang;Wan, Yingchun;Li, Tao
静脉麻醉剂丙泊酚在癌症中的生物学作用已通过使用代表分化癌细胞的癌细胞系的各种研究显示。然而，丙泊酚在癌症干细胞中的活性尚未阐明。本研究旨在探讨异丙酚对急性髓系白血病（AML）分化细胞和CD 34（+）CD 38（-）干细胞的作用及其机制。我们发现，异丙酚抑制AML干细胞的生长，分化和自我更新能力，而不管细胞来源和遗传特征如何。此外，丙泊酚抑制AML分化细胞的生长。异丙酚可显著诱导AML分化干细胞凋亡，但对CD 34（+）CD 38（-）干细胞无明显影响。我们进一步发现丙泊酚显著增强了AML标准治疗药物的疗效。与之前的研究结果一致，我们发现丙泊酚抑制AML细胞中的Akt/mTOR通路。我们还发现，丙泊酚抑制了对干细胞维持和自我更新重要的途径，如Wnt/β-连环蛋白。组成性激活Akt的过表达部分逆转了丙泊酚对AML分化细胞的抑制作用。使用遗传和药理学方法稳定β-连环蛋白也部分挽救了丙泊酚在AML分化细胞和干细胞中的抑制作用。我们的工作表明，异丙酚靶向白血病细胞在所有阶段的发展，在细胞类型特异性的方式。抑制Akt/mTOR和Wnt/β-连环蛋白是丙泊酚在AML中发挥作用所必需的。我们的研究结果还强调了异丙酚对癌症干细胞的作用。
The biological roles of intravenous anaesthetic propofol in cancer have been shown by various studies using cancer cell lines that represent differentiated cancer cells. However, the activities of propofol in cancer stem cells have not been elucidated. In this work, we examined the effects and mechanisms of propofol on acute myeloid leukaemia (AML) differentiated and CD34(+)CD38(-) stem cells. We found that propofol inhibited growth, differentiation and self-renewal capabilities of AML stem cells regardless of cellular origin and genetic profiling. In addition, propofol inhibited the growth of AML differentiated cells. Propofol significantly induced apoptosis of AML differentiated but not CD34(+)CD38(-) stem cells. We further found that propofol significantly augmented the efficacy of AML standard therapeutic drugs. Consistent with the previous findings, we showed that propofol suppressed the Akt/mTOR pathway in AML cells. We also found that propofol inhibited pathways important for stem cell maintenance and self-renewal, such as Wnt/beta-catenin. Overexpression of constitutively active Akt partially reversed the inhibitory effects of propofol in AML differentiated cells. Stabilization of beta-catenin using genetic and pharmacological approaches also partially rescued the inhibitory effects of propofol in AML differentiated and stem cells. Our work shows that propofol targets leukaemia cells at all stages of development, in a cell type-specific manner. Inhibition of both Akt/mTOR and Wnt/beta-catenin is required for the action of propofol in AML. Our findings also highlight the activities of propofol on cancer stem cells.