Cyclovirobuxine D Exerts Anticancer Effects by Suppressing the EGFR-FAK-AKT/ERK1/2-Slug Signaling Pathway in Human Hepatocellular Carcinoma
Cyclovirobuxine D Exerts Anticancer Effects by Suppressing the EGFR-FAK-AKT/ERK1/2-Slug Signaling Pathway in Human Hepatocellular Carcinoma
复制标题
环维黄杨星 D 通过抑制人肝细胞癌中的 EGFR-FAK-AKT/ERK1/2-Slug 信号通路发挥抗癌作用
DOI：
10.1089/dna.2019.4990
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发表时间：
2020
影响因子：
3.1
通讯作者：
Yang Xiuhua
中科院分区：
文献类型：
--
作者：
Zhang Jiuwei;Chen Yaodong;Lin Jing;Jia Ruimei;An Tingting;Dong Tianxiu;Zhang Yu;Yang Xiuhua
肝细胞癌（HCC）是世界上第六大最常见的恶性肿瘤，其特点是由于高复发和转移率而预后不佳。因此，迫切需要开发新的化疗药物。环维黄柏碱D （Cyclovirobuxine D, CVB-D）是一种从小叶黄柏中提取的甾体生物碱，被广泛用于缓解心血管疾病的症状，在最近的研究中显示出很好的抗肿瘤作用。然而，CVB-D对HCC的治疗效果和潜在机制在很大程度上仍不清楚。本实验表明，CVB-D可通过阻滞G2期细胞周期抑制HCC细胞增殖，促进细胞凋亡。此外，非致死剂量的cbc - d显著减弱了HCC细胞的迁移和侵袭能力，这种减弱与上皮-间质转化（EMT）的抑制有关。此外，在体内，CVB-D在HCC荷瘤裸鼠中显示出良好的抗癌作用。关于cbb - d活性的分子机制，我们确定slugg表达的降低与上述提取物的抗hcc功能有关，这可能是由表皮生长因子受体（EGFR）通过局灶黏附激酶（FAK）相关的pi3k /AKTandMEK/ erk1 /2信号通路调控的。综上所述，我们的研究结果揭示了cbc - d对HCC进展行为的抑制作用，包括增殖、迁移、侵袭和EMT，以及其突出的促凋亡作用，这与抑制egfr - fak - akt / erk1 /2- slug信号通路有关。这些发现为使用CVB-D作为HCC治疗的有希望的候选药物提供了实验和理论基础。
Hepatocellular carcinoma (HCC), the sixth most common malignancy worldwide, is characterized by a dismal prognosis due to high recurrence and metastasis rates. Thus, the need for the development of novel chemotherapeutic drugs is urgent. Cyclovirobuxine D (CVB-D), a steroidal alkaloid extracted fromBuxus microphyllathat has been extensively used to relieve the symptoms of cardiovascular diseases, has shown promising antineoplastic effects in recent studies. However, the therapeutic effects and underlying mechanisms of CVB-D on HCC remain largely unelucidated. This study experimentally indicated that CVB-D can repress HCC cell proliferation by arresting the cell cycle in G2 phase and can facilitate apoptosis. In addition, the migratory and invasive capabilities of HCC cells were noticeably attenuated by a nonlethal dose of CVB-D, and this attenuation was correlated with the inhibition of epithelial–mesenchymal transition (EMT). Moreover,in vivo, CVB-D displayed excellent anticancer effects in HCC tumor-bearing nude mice. Regarding the molecular mechanisms of CVB-D activity, decreasedSlugexpression was determined to be associated with the aforementioned anti-HCC functions of this extract, which might be regulated by epidermal growth factor receptor (EGFR) through the focal adhesion kinase (FAK)-associatedPI3K/AKTandMEK/ERK1/2signaling pathways. Collectively, our results revealed the suppressive effects of CVB-D on progressive behaviors of HCC, including proliferation, migration, invasion, and EMT, in addition to its outstanding proapoptotic effects, which were correlated with the inhibition of theEGFR-FAK-AKT/ERK1/2-Slugsignaling pathway. These discoveries provide an experimental and theoretical foundation for the use of CVB-D as a promising candidate for HCC therapy.