Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells.
Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells.
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小白菊内酯通过 TNFRSF10B 和 PMAIP1 途径诱导人肺癌细胞凋亡。
DOI：
10.1186/1756-9966-33-3
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发表时间：
2014-01-06
期刊：
影响因子：
--
通讯作者：
Su L
中科院分区：
文献类型：
--
作者：
Zhao X;Liu X;Su L
银胶菊（Parthenopropylene，PTL）是一种倍半萜内酯类化合物，能诱导肿瘤细胞凋亡，并能清除白血病干细胞、前列腺肿瘤起始细胞等肿瘤干细胞，但其作用机制尚不清楚。用孤雌菊处理肺癌细胞，制备细胞裂解液，用Western Blot分析蛋白质的表达，用SRB和MTT法检测细胞存活率。流式细胞术检测细胞周期;采用siRNA技术敲除TNFRSF 10 B、PMAIP 1、ATF 4和DDIT 3基因。Annexin V-FITC/PI双染及流式细胞术检测细胞凋亡。银胶菊（PTL）诱导人肺癌细胞凋亡和细胞周期阻滞。此外，PTL处理NSCLC细胞会增加TNFRSF 10 B/DR 5和PMAIP 1/NOXA的表达。TNFRSF 10 B或PMAIP 1的沉默或CFLAR /c-FLIP（长型）的过表达可以保护细胞免受PTL诱导的凋亡。此外，PTL可增加内质网应激标志物如ERN 1、HSPA 5、p-EIF 2A、ATF 4和DDIT 3的水平。ATF 4和DDIT 3的敲低可阻断PTL诱导的细胞凋亡，提示PTL通过激活内质网应激途径诱导NSCLC细胞凋亡。更重要的是，我们发现PTL在A549/shCDH 1细胞中更强烈地上调ATF 4、DDIT 3、TNFRSF 10 B和PMAIP 1，而更显著地下调CFLAR和MCL 1，这表明PTL更倾向于通过激活癌干细胞样细胞中更强烈的ER应激反应来杀死癌干细胞样细胞。结果表明，孤雌菊不仅通过上调TNFRSF 10 B和下调CFLAR来诱导细胞发生外源性凋亡，而且通过上调PMAIP 1的表达和降低MCL 1的水平来诱导细胞发生内源性凋亡。此外，孤雌菊在癌干细胞样细胞中引发更强的ER应激反应，这导致其在凋亡诱导中的偏好。总之，PTL通过激活内质网应激反应诱导NSCLC细胞凋亡。
Parthenolide (PTL) is a sesquiterpene lactone which can induce apoptosis in cancer cells and eradicate cancer stem cells such as leukemia stem cells, prostate tumor-initiating cells and so on. However, the mechanism remains largely unclear. Lung cancer cells were treated with parthenolide and the cell lysates were prepared to detect the given proteins by Western Blot analysis, and the cell survival was assayed by SRB and MTT assay. Cell cycle was evaluated by DNA flow cytometry analysis. TNFRSF10B, PMAIP1, ATF4 and DDIT3 genes were knocked down by siRNA technique. Apoptosis was evaluated by using Annexin V-FITC/PI staining and flow cytometry analysis. Parthenolide (PTL) induces apoptosis and cell cycle arrest in human lung cancer cells. Moreover, PTL treatment in NSCLC cells increases expression of TNFRSF10B/DR5 and PMAIP1/NOXA. Silencing of TNFRSF10B or PMAIP1 or overexpression of CFLAR /c-FLIP (long form) could protect cells from PTL-induced apoptosis. Furthermore, PTL could increase the levels of endoplasmic reticulum stress hallmarks such as ERN1, HSPA5, p-EIF2A, ATF4 and DDIT3. Knockdown of ATF4 and DDIT3 abrogated PTL-induced apoptosis, which suggested that PTL induced apoptosis in NSCLC cells through activation of endoplasmic reticulum stress pathway. More importantly, we found that ATF4, DDIT3, TNFRSF10B and PMAIP1 were up-regulated more intensively, while CFLAR and MCL1 were down-regulated more dramatically by PTL in A549/shCDH1 cells than that in control cells, suggesting that PTL preferred to kill cancer stem cell-like cells by activating more intensive ER stress response in cancer stem cell-like cells. We showed that parthenolide not only triggered extrinsic apoptosis by up-regulating TNFRSF10B and down-regulating CFLAR, but also induced intrinsic apoptosis through increasing the expression of PMAIP1 and decreasing the level of MCL1 in NSCLC cells. In addition, parthenolide triggered stronger ER stress response in cancer stem cell-like cells which leads to its preference in apoptotic induction. In summary, PTL induces apoptosis in NSCLC cells by activating endoplasmic reticulum stress response.
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DOI：
10.1186/1756-9966-29-108
发表时间：
2010-08-10
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Liu JW;Cai MX;Xin Y;Wu QS;Ma J;Yang P;Xie HY;Huang DS
通讯作者：
Huang DS
影响因子：
2.6
作者：
Schroeder, Martin
通讯作者：
Schroeder, Martin
影响因子：
21.3
作者：
Feng, B;Yao, PM;Tabas, I
通讯作者：
Tabas, I
影响因子：
3.3
作者：
Schinella, GR;Giner, RM;Máñez, S
通讯作者：
Máñez, S
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES