Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell
Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell
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Lanatoside C 通过减弱人胃癌细胞中 Wnt/β-catenin/c-Myc 信号通路抑制细胞增殖并诱导细胞凋亡
DOI：
10.1016/j.bcp.2018.02.023
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发表时间：
2018-04-01
影响因子：
5.8
通讯作者：
Qian, Feng
中科院分区：
文献类型：
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作者：
Hu, Yudong;Yu, Kaikai;Qian, Feng
胃癌是世界上第三大恶性肿瘤，由于缺乏有效的治疗手段，其预后差，复发率高。我们的研究表明，毛花苷C，FDA批准的强心苷，对不同的人癌细胞系（MKN-45; SGC-7901; HN 4; MCF-7; HepG 2）具有抗增殖作用，并且胃细胞系MKN-45和SGC-7901是毛花苷C最敏感的细胞系。毛花苷C可使MKN-45细胞周期阻滞于G2/M期，并抑制细胞迁移。同时，caspase-9和PARP的表达上调，Bcl-xl的表达下调，线粒体膜电位（MMP）降低，细胞内活性氧（ROS）增加。毛花苷C通过下调c-Myc抑制Wnt/beta-catenin信号传导，而过表达c-Myc则逆转毛花苷C的抗肿瘤作用，证实c-Myc是毛花苷C的关键药物靶点。此外，我们还发现毛花苷C可通过蛋白酶体-泛素途径促进c-Myc的降解，并减弱USP 28与c-Myc的结合。这些发现表明毛花苷C靶向c-Myc泛素化以抑制MKN-45增殖，并支持毛花苷C作为化疗候选物的潜在价值。
Gastric cancer is the third common cause of cancer mortality in the world with poor prognosis and high recurrence due to lack of effective medicines. Our studies revealed that lanatoside C, a FDA-approved cardiac glycoside, had an anti-proliferation effect on different human cancer cell lines (MKN-45; SGC-7901; HN4; MCF-7; HepG2) and gastric cell lines MKN-45 and SGC-7901 were the most sensitive cell lines to lanatoside C. MKN-45 cells treated with lanatoside C showed cell cycle arrest at G2/M phase and inhibition of cell migration. Meanwhile, upregulation of cleaved caspase-9 and cleaved PARP and downregulation of Bcl-xl were accompanied with the loss of mitochondria' membrane potential (MMP) and induction of intracellular reactive oxygen species (ROS). Lanatoside C inhibited Wnt/beta-catenin signaling with downregulation of c-Myc, while over expression of c-Myc reversed the anti-tumor effect of lanatoside C, confirming that c-Myc is a key drug target of lanatoside C. Furthermore, we discovered that lanatoside C prompted c-Myc degradation in proteasome-ubiquitin pathway with attenuating the binding of USP28 to c-Myc. These findings indicate that lanatoside C targeted c-Myc ubiquitination to inhibit MKN-45 proliferation and support the potential value of lanatoside C as a chemotherapeutic candidate.