Paclitaxel suppresses proliferation and induces apoptosis through regulation of ROS and the AKT/MAPK signaling pathway in canine mammary gland tumor cells.
Paclitaxel suppresses proliferation and induces apoptosis through regulation of ROS and the AKT/MAPK signaling pathway in canine mammary gland tumor cells.
复制标题
紫杉醇通过调节 ROS 和 AKT/MAPK 信号通路抑制犬乳腺肿瘤细胞增殖并诱导细胞凋亡
DOI：
10.3892/mmr.2018.8868
复制
发表时间：
2018-06
影响因子：
3.4
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Ren X;Zhao B;Chang H;Xiao M;Wu Y;Liu Y
紫杉醇是一种二萜类化合物，来源于太平洋紫杉（Taxus brevifolia）浆果，对各种类型的癌症具有抗癌作用。然而，紫杉醇对犬CHMm细胞的抗肿瘤作用和分子机制仍有待阐明。本研究采用MTT法、流式细胞术、吖啶橙子/溴化乙锭染色、透射电镜、细胞活性氧（ROS）、超氧化物歧化酶（SOD）和丙二醛（MDA）的测定以及Western印迹等方法，研究紫杉醇对CHMm细胞的抗肿瘤作用，并探讨紫杉醇对CHMm细胞的相关信号转导通路的调控。数据表明紫杉醇以剂量依赖性方式降低细胞活力，诱导G2/M期细胞周期停滞，抑制细胞周期蛋白B1的表达并诱导凋亡。此外，紫杉醇还可上调Bax和细胞色素c的表达，降低凋亡调节因子Bcl-2的表达，导致caspase-3活化，染色质浓缩，核固缩，细胞内空泡化，ROS和MDA产生增加，SOD活性降低。然而，当CHMm细胞用N-乙酰-L-半胱氨酸处理时，这些作用被抑制。此外，紫杉醇还可抑制CHMm细胞中磷酸化（p）-RAC-α丝氨酸/苏氨酸蛋白激酶（AKT）和p-核糖体蛋白S6激酶蛋白的水平，促进P38丝裂原活化蛋白激酶（MAPK）和p-90 kDa核糖体蛋白S6激酶1蛋白的磷酸化。观察到紫杉醇与P38和磷脂酰肌醇-4，5-二磷酸3-激酶（PI 3 K）信号传导途径的药理学抑制剂（分别为SB 203580和LY 294002）组合对CHMm细胞的增殖产生协同抑制作用。本研究结果表明，紫杉醇通过抑制PI 3 K/AKT信号通路和激活MAPK信号通路增加CHMm细胞的内源性凋亡来抑制肿瘤细胞增殖。
Paclitaxel is a diterpenoid compound, derived from the pacific yew (Taxus brevifolia) berry, which exhibits antineoplastic effects against various types of cancer. However, the antitumor effects and the molecular mechanisms of paclitaxel on canine CHMm cells remain to be elucidated. The aim of the present study was to investigate the antitumor effects of paclitaxel on CHMm cells and identify relevant signal transduction pathways modulated by paclitaxel using multiple methods including MTT assay, flow cytometry, acridine orange/ethidium bromide staining, transmission electron microscopy, determination of cellular reactive oxygen species (ROS), superoxide dismutase (SOD) and malondiadehyde (MDA) and western blotting, the data indicated that paclitaxel decreased cell viability, induced G2/M-phase cell cycle arrest, suppressed the expression of cyclin B1 and induced apoptosis in a dose-dependent manner. In addition, paclitaxel upregulated the expression of Bax and cytochrome c, but reduced expression of apoptosis regulator Bcl-2, resulting in activation of caspase-3, chromatin condensation, karyopyknosis, intracellular vacuolization, increased production of ROS and MDA, and decreased activity of SOD. However, these effects were inhibited when CHMm cells were treated with N-acetyl-L-cysteine. Furthermore, treatment with paclitaxel inhibited the level of of phospho (p)-RAC-α serine/threonine-protein kinase (AKT) and p-ribosomal protein S6 kinase proteins, and promoted phosphorylation of P38 mitogen-activated protein kinase (MAPK) and p-90 kDa ribosomal protein S6 kinase 1 proteins in CHMm cells. It was observed that paclitaxel in combination with pharmacological inhibitors of the P38 and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling pathways (SB203580 and LY294002, respectively) exerted synergistic inhibitory effects on the proliferation of the CHMm cells. The results of the present study demonstrated that paclitaxel inhibited tumor cell proliferation by increasing intrinsic apoptosis through inhibition of the PI3K/AKT signaling pathway and activation of MAPK signaling pathway in CHMm cells.
登录
查看更多内容
影响因子：
64.8
作者：
SCHIFF, PB;FANT, J;HORWITZ, SB
通讯作者：
HORWITZ, SB
DOI：
10.1165/rcmb.2009-0094oc
发表时间：
2010-05-01
影响因子：
6.4
作者：
Azad, Neelam;Iyer, Anand Krishnan V.;Rojanasakul, Yon
通讯作者：
Rojanasakul, Yon
影响因子：
3
作者：
Sakashita, Fumio;Osada, Shinji;Seishima, Mitsuru
通讯作者：
Seishima, Mitsuru
DOI：
10.1155/2011/792639
发表时间：
2011
期刊：
Journal of signal transduction
影响因子：
--
作者：
Son Y;Cheong YK;Kim NH;Chung HT;Kang DG;Pae HO
通讯作者：
Pae HO
DOI：
10.1093/jnci/83.24.1797-a
发表时间：
1991-12-18
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
HOLMES, FA;WALTERS, RS;HORTOBAGYI, GN
通讯作者：
HORTOBAGYI, GN