Fomitoside-K from Fomitopsis nigra Induces Apoptosis of Human Oral Squamous Cell Carcinomas (YD-10B) via Mitochondrial Signaling Pathway
Fomitoside-K from Fomitopsis nigra Induces Apoptosis of Human Oral Squamous Cell Carcinomas (YD-10B) via Mitochondrial Signaling Pathway
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DOI：
10.1248/bpb.b12-00297
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发表时间：
2012-10-01
影响因子：
2
通讯作者：
Yi, Ho-Keun
中科院分区：
文献类型：
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作者：
Bhattarai, Govinda;Lee, Young-Hee;Yi, Ho-Keun
本研究从蘑菇黑Fomitopsis nigra中分离出一种新的具有生物活性分子的毛甾烷三萜苷（fomitoside-K），并检测其对人口腔鳞状细胞癌（YD-10B）的抗癌活性。我们重点研究了fomitoside-K对YD-10B细胞凋亡、线粒体介导的死亡途径和活性氧（ROS）积累的影响。Fomitoside-K可诱导pd - 10b细胞发生剂量依赖性和时间依赖性的凋亡，表现为细胞形态、细胞周期阻滞、survivin抑制、多聚adp核糖聚合酶（PARP）、caspase-3、-9活化以及Bax/Bcl-2表达比升高。在诱导过程中观察到线粒体膜电位损失和细胞色素c （Cyt c）从线粒体向细胞质溶胶释放。此外，fomitoside-K在YD-10B细胞中引起细胞内ROS水平的剂量依赖性升高，并增加c-Jun n -末端激酶（JNK）和细胞外信号调节激酶（ERK）的磷酸化。为了进一步研究其机制，我们研究了活性氧清除剂n -乙酰- l-半胱氨酸（NAC）和丝裂原活化蛋白激酶（MAPK）途径的选择性抑制剂对细胞死亡的影响。NAC、ERK （PD98059）和JNK抑制剂（SP600125）均能显著抑制虫霉苷k由ROS诱导的细胞死亡。此外，fomitoside-K与阿霉素具有协同抑制YD-10B细胞生长的作用。这些数据表明，fomitoside-K通过ros依赖的线粒体功能障碍途径诱导YD-10B细胞凋亡，为进一步探索fomitoside-K对人类口腔癌增殖的抑制作用提供了机制框架。
In this study, a new lanostane triterpene glycoside (fomitoside-K) having biologically active molecules was isolated from a mushroom Fomitopsis nigra to test its anticancer activity on human oral squamous cell carcinomas (YD-10B). We focused on the effect of fomitoside-K on apoptosis, the mitochondria-mediated death pathway and the accumulation of reactive oxygen species (ROS) in YD-10B cells. Fomitoside-K could induce a dose and time-dependent apoptosis in YD-10B cells as characterized by cell morphology, cell cycle arrest, inhibition of survivin, activation of poly(ADP-ribose) polymerase (PARP), caspase-3, -9 and an increased expression ratio of Bax/Bcl-2. The mitochondria membrane potential loss and cytochrome c (Cyt C) release from mitochondria to cytosol were observed during the induction. Moreover, fomitoside-K caused dose-dependent elevation of intracellular ROS level and increase phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) in YD-10B cells. To further investigate the mechanisms, we examined the effects of ROS scavenger N-acetyl-L-cysteine (NAC) and selective inhibitors for mitogen activated protein kinase (MAPK) pathways on the cell death. The fomitoside-K induced cell death by ROS was significantly inhibited by NAC, ERK (PD98059) and JNK inhibitor (SP600125). In addition, fomitoside-K has a synergistic effect with adriamycin in suppressing the growth of YD-10B cells. These data suggest that fomitoside-K induces apoptosis in YD-10B cells through the ROS-dependent mitochondrial dysfunction pathway and provides a mechanistic framework for further exploring the use of fomitoside-K against the proliferation of human oral cancer.