Wang Zhuangqiang, Cui Xiaopeng, Hao Gaopeng, He Jiefeng
Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, No. 99 Longcheng Street, Taiyuan 030032, Shanxi, China.
Department of General Surgery, Shanxi Provincial People's Hospital, Taiyuan 030032, Shanxi, China.
Open Life Sci. 2021 Sep 27;16(1):1037-1044. doi: 10.1515/biol-2021-0101. eCollection 2021.
Phosphatidylinositol 3-kinase (PI3K)/AKT signaling is a crucial pathway for cell survival and proliferation, which are regulated by several growth factors and activated receptors. Upregulated PI3K/AKT signaling molecules were reported in several cancers and they are associated with altered cellular functions, leading to oncogenesis. Here, we have examined the implications of elevated PI3K/AKT expression in the apoptosis resistance of human hepatocellular carcinoma (HCC) Huh7 cells. We showed that PI3K/AKT signaling is significantly upregulated in Huh7 cells by quantitative polymerase chain reaction and protein expression analysis. Also, perversely upregulated PI3K/AKT signaling Huh7 cells are highly resistant to treatment with chemotherapy drugs (docetaxel and sorafenib) and acquired apoptosis resistance through downregulation of tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome ten). Hence, we have investigated the effect of PTEN overexpression on apoptosis induction in Huh7 cells. We showed that PTEN overexpressed Huh7 cells became more sensitive toward the aforesaid drugs and induced apoptotic cell death due to intracellular reactive oxygen species (ROS) generation. Concurrently, the overexpression of PTEN leads to the activation of mitochondria facilitated intrinsic apoptosis, evidenced by upregulated cytochrome C, caspase 3, and caspase 9. Collectively, our data suggest that the aberrant expression of PI3K/AKT signaling contributes to apoptosis resistance in HCC.
磷脂酰肌醇3激酶（PI3K）/AKT信号通路是细胞存活和增殖的关键途径，受多种生长因子和激活受体的调控。在几种癌症中均报道了PI3K/AKT信号分子上调，它们与细胞功能改变有关，从而导致肿瘤发生。在此，我们研究了PI3K/AKT表达升高对人肝癌（HCC）Huh7细胞凋亡抗性的影响。通过定量聚合酶链反应和蛋白质表达分析，我们发现Huh7细胞中PI3K/AKT信号通路显著上调。此外，PI3K/AKT信号通路异常上调的Huh7细胞对化疗药物（多西他赛和索拉非尼）治疗具有高度抗性，并通过下调肿瘤抑制蛋白PTEN（第10号染色体上缺失的磷酸酶和张力蛋白同源物）获得凋亡抗性。因此，我们研究了PTEN过表达对Huh7细胞凋亡诱导的影响。我们发现PTEN过表达的Huh7细胞对上述药物变得更加敏感，并由于细胞内活性氧（ROS）的产生而诱导凋亡性细胞死亡。同时，PTEN的过表达导致线粒体促进的内源性凋亡激活，细胞色素C、半胱天冬酶3和半胱天冬酶9的上调证明了这一点。总体而言，我们的数据表明PI3K/AKT信号通路的异常表达导致HCC细胞凋亡抗性。
