Lupeol Targets Liver Tumor-Initiating Cells Through Phosphatase and Tensin Homolog Modulation
Lupeol Targets Liver Tumor-Initiating Cells Through Phosphatase and Tensin Homolog Modulation
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DOI：
10.1002/hep.24000
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发表时间：
2011-01-01
期刊：
影响因子：
13.5
通讯作者：
Ng, Irene Oi Lin
中科院分区：
文献类型：
--
作者：
Lee, Terence Kin Wah;Castilho, Antonia;Ng, Irene Oi Lin
肝肿瘤起始细胞（T-IC）能够自我更新和肿瘤起始，并且对化疗药物更具化学抗性。因此，目前针对干细胞自我更新途径的治疗策略代表了癌症预防和治疗的合理方法。在本研究中，我们发现Lup-20（29）-en-3 beta-ol（羽扇豆醇），一种在水果和蔬菜中发现的三萜，抑制肝细胞癌（HCC）细胞系和临床HCC样品中存在的肝T-IC的自我更新能力，如肝球形成所反映的。此外，羽扇豆醇抑制裸鼠体内致瘤性并下调CD 133表达，CD 133表达先前被证明是HCC的T-IC标志物。此外，羽扇豆醇通过磷酸酶和张力蛋白同源物（PTEN）-Akt-ABCG 2途径使HCC细胞对化疗药物敏感。PTEN在肝脏T-IC的自我更新和化学抗性中起着至关重要的作用;通过基于慢病毒的方法下调PTEN逆转了羽扇豆醇对肝脏T-IC的作用。使用体内化学抗性HCC肿瘤模型，羽扇豆醇显著降低MHCC-LM 3 HCC细胞系衍生的异种移植物的肿瘤体积，并且效果与顺铂和多柔比星联合治疗的效果相当。羽扇豆醇与化疗药物联合使用时，具有协同作用，对体重无任何不良影响。结论：我们的研究结果表明羽扇豆醇可能是一种有效的膳食植物化学物质，靶向肝脏T-IC。（肝脏学2011;53：160-170）
Liver tumor-initiating cells (T-ICs) are capable of self-renewal and tumor initiation and are more chemoresistant to chemotherapeutic drugs. The current therapeutic strategies for targeting stem cell self-renewal pathways therefore represent rational approaches for cancer prevention and treatment. In the present study, we found that Lup-20(29)-en-3 beta-ol (lupeol), a triterpene found in fruits and vegetables, inhibited the self-renewal ability of liver T-ICs present in both hepatocellular carcinoma (HCC) cell lines and clinical HCC samples, as reflected by hepatosphere formation. Furthermore, lupeol inhibited in vivo tumorigenicity in nude mice and down-regulated CD 133 expression, which was previously shown to be a T-IC marker for HCC. In addition, lupeol sensitized HCC cells to chemotherapeutic agents through the phosphatase and tensin homolog (PTEN)-Akt-ABCG2 pathway. PTEN plays a crucial role in the self-renewal and chemoresistance of liver T-ICs; down-regulation of PTEN by a lentiviral-based approach reversed the effect of lupeol on liver T-ICs. Using an in vivo chemoresistant HCC tumor model, lupeol dramatically decreased the tumor volumes of MHCC-LM3 HCC cell line-derived xenografts, and the effect was equivalent to that of combined cisplatin and doxorubicin treatment. Lupeol exerted a synergistic effect without any adverse effects on body weight when combined with chemotherapeutic drugs. Conclusion: Our results suggest that lupeol may be an effective dietary phytochemical that targets liver T-ICs. (HEPATOLOGY 2011;53:160-170)