20(S)-Protopanaxadiol Triggers Mitochondrial-Mediated Apoptosis in Human Lung Adenocarcinoma A549 Cells via Inhibiting the PI3K/Akt Signaling Pathway
20(S)-Protopanaxadiol Triggers Mitochondrial-Mediated Apoptosis in Human Lung Adenocarcinoma A549 Cells via Inhibiting the PI3K/Akt Signaling Pathway
复制标题
20(S)-原人参二醇通过抑制 PI3K/Akt 信号通路触发人肺腺癌细胞 A549 中线粒体介导的细胞凋亡
DOI：
10.1142/s0192415x13500778
复制
发表时间：
2013-01-01
影响因子：
5.7
通讯作者：
Sui, Da-Yuan
中科院分区：
文献类型：
--
作者：
Zhang, Yun-Long;Zhang, Rui;Sui, Da-Yuan
20（S）-原人参二醇（PPD）是从西洋参中分离的一种糖苷配基皂苷，具有抑制多种肿瘤细胞生长和增殖的作用。然而，潜在的分子机制仍然知之甚少。本研究探讨了20（S）-PPD对人肺腺癌A549细胞的凋亡诱导作用及其机制。20（S）-PPD通过诱导A549细胞凋亡而显示出有效的抗增殖活性。20（S）-PPD诱导的细胞凋亡的特征在于剂量依赖性的线粒体膜损失、细胞色素c、第二类caspase衍生激活物（Smac）和凋亡诱导因子（AIF）的释放、caspase-9/-3的激活和聚（ADP-核糖）聚合酶（PARP）的裂解。半胱天冬酶依赖性通过泛半胱天冬酶抑制剂z-VAD-favorite减弱20（S）-PPD诱导的细胞凋亡的能力来指示。20（S）-PPD处理后，A549细胞G 0/G1期比例增加，S期和G2/M期比例减少。此外，20（S）-PPD还引发磷酸化Akt（Ser 473/Thr 308）和糖原合成酶激酶3 β（GSK 3 β）的下调。用siRNA敲低GSK 3 β可促进20（S）-PPD的凋亡作用。这些结果揭示了这种独特的药物的一种意想不到的作用机制：通过下调A549细胞中的PI 3 K/Akt信号通路，引发细胞介导的半胱天冬酶依赖性凋亡。我们的研究结果鼓励进一步研究20（S）-PPD作为一种有前途的肺癌化学预防剂。
20(S)-Protopanaxadiol (PPD), an aglycone saponin ginsenoside isolated from Panax quinquefolium L, has been shown to inhibit the growth and proliferation in several cancer lines. However, the underlying molecular mechanisms remain poorly understood. In this study, we investigated the apoptosis-induced effects and the mechanism of 20(S)-PPD on human lung adenocarcinoma A549 cells. 20(S)-PPD showed a potent antiproliferative activity against A549 cells by triggering apoptosis. 20(S)-PPD-induced apoptosis was characterized by a dose-dependent loss of the mitochondrial membrane, release of cytochrome c, second mitochondria-derived activator of caspase (Smac) and apoptosis-inducing factor (AIF), activation of caspase-9/-3, and cleavage of poly (ADP-ribose) polymerase (PARP). Caspase-dependence was indicated by the ability of the pan-caspase inhibitor z-VAD-fmk to attenuate 20(S)-PPD-induced apoptosis. After treatment with 20(S)-PPD, the proportion of A549 cells at the G0/G1 phase increased, while cells at the S and G2/M phases decreased. Furthermore, 20(S)-PPD also triggered down-regulation of phosphorylated Akt (Ser473/Thr308) and glycogen synthase kinase 3 beta (GSK 3 beta). Knockdown of GSK 3 beta with siRNA promoted the apoptotic effects of 20(S)-PPD. These results revealed an unexpected mechanism of action for this unique ginsenoside: triggering a mitochondrial-mediated, caspase-dependent apoptosis via down-regulation of the PI3K/Akt signaling pathway in A549 cells. Our findings encourage further studies of 20(S)-PPD as a promising chemopreventive agent against lung cancer.