Induction of Hepatocellular Carcinoma Cell Cycle Arrest and Apoptosis by Dendropanax morbifera Leveille Leaf Extract via the PI3K/AKT/mTOR Pathway.

IF 2.5 Q3 ONCOLOGY
Gi Dae Kim
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Abstract

Liver cancer is prevalent worldwide and associated with a high mortality rate. Therefore, developing novel drugs derived from natural products to reduce the side effects of chemotherapy is urgently needed. In this study, the inhibitory effect of Dendropanax morbifera Leveille extract (DME) on growth of hepatocellular carcinoma (HCC) cells and its underlying mechanisms were investigated. DME suppressed the growth, migration, and invasion of SK-Hep1 human HCC cells. It also reduced the expression of the G0/G1 phase regulator proteins cyclin-dependent kinase (CDK) 4, cyclin D, CDK2, and cyclin E, thereby inducing G0/G1 arrest. Moreover, DME treatment reduced the expression of antiapoptotic proteins, including caspase-9, caspase-3, PARP, and Bcl-2 and increased the expression of the proapoptotic protein, Bax. DME also increased reactive oxygen species production and reduced the cellular uptake of rhodamine 123. DME treatment increased the levels of p-p38 and p-FOXO3a in a dose-dependent manner and decreased those of p-PI3K, p-AKT, p-mTOR, and p-p70 in SK-Hep1 cells. In addition, combined treatment with DME and LY294002, an AKT inhibitor, significantly reduced p-AKT levels. In summary, these results show that the PI3K/AKT/mTOR signaling pathway is involved in DME-mediated inhibition of proliferation, migration, and invasiveness, and induction of apoptosis of HCC cells.

Dendropanax morbifera Leveille Leaf Extract 通过 PI3K/AKT/mTOR 途径诱导肝细胞癌细胞周期停滞和凋亡
肝癌在全世界都很普遍,死亡率也很高。因此,开发从天然产品中提取的新型药物以减少化疗的副作用迫在眉睫。本研究探讨了Dendropanax morbifera Leveille提取物(DME)对肝癌(HCC)细胞生长的抑制作用及其内在机制。DME 抑制了 SK-Hep1 人 HCC 细胞的生长、迁移和侵袭。它还能降低G0/G1期调节蛋白细胞周期蛋白依赖性激酶(CDK)4、细胞周期蛋白D、CDK2和细胞周期蛋白E的表达,从而诱导G0/G1期停滞。此外,DME还降低了抗凋亡蛋白(包括caspase-9、caspase-3、PARP和Bcl-2)的表达,增加了促凋亡蛋白Bax的表达。二甲胺肿还增加了活性氧的产生,减少了细胞对罗丹明123的吸收。在SK-Hep1细胞中,DME以剂量依赖的方式增加了p-p38和p-FOXO3a的水平,降低了p-PI3K、p-AKT、p-mTOR和p-p70的水平。此外,DME 和 AKT 抑制剂 LY294002 联合治疗可显著降低 p-AKT 水平。总之,这些结果表明,PI3K/AKT/mTOR 信号通路参与了 DME 介导的 HCC 细胞增殖、迁移、侵袭性抑制和凋亡诱导。
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