XIAP antagonist embelin inhibited proliferation of cholangiocarcinoma cells.
XIAP antagonist embelin inhibited proliferation of cholangiocarcinoma cells.
复制标题
DOI：
10.1371/journal.pone.0090238
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Mott JL
中科院分区：
文献类型：
--
作者：
Wehrkamp CJ;Gutwein AR;Natarajan SK;Phillippi MA;Mott JL
胆管癌细胞的存活和对死亡刺激的抵抗依赖于抗凋亡信号。最近的机制研究表明，E3泛素蛋白连接酶X连锁凋亡抑制物(XIAP)的细胞表达增加，削弱了TRAIL和化疗诱导的细胞毒作用，促进了胆管癌细胞的存活。本研究旨在确定XIAP蛋白的药理拮抗作用是否足以使胆管癌细胞对细胞死亡敏感。我们使用恶性胆管癌细胞系，并使用Embelin来拮抗XIAP蛋白。恩贝林处理KMCH和Mz-CHA-1细胞8小时后，XIAP蛋白水平降低，16小时作用最强。对细胞核形态的评估表明，随着浓度的增加，细胞核染色增加。有趣的是，恩贝林作为单一诱导剂诱导细胞核形态改变，与添加肿瘤坏死因子相关的凋亡诱导配体(TRAIL)无关。然而，caspase活性分析表明，增加embelin浓度会导致caspase活性的轻微抑制，而不是激活。此外，使用泛caspase抑制剂并不能阻止细胞核形态的改变。最后，恩贝林处理胆管癌细胞不会引起DNA断裂或PARP裂解。细胞凋亡似乎与恩贝林对胆管癌细胞的作用无关。反之，恩贝林对细胞增殖有抑制作用，细胞周期分析显示恩贝林增加了S和G2/M期细胞的数量。我们的结果表明恩贝林抑制了胆管癌细胞系的增殖。Embelin可降低XIAP蛋白的表达，但不能诱导或促进细胞凋亡。因此，在胆管癌细胞中，Embelin的作用机制可能不依赖于细胞凋亡。
Cholangiocarcinoma cells are dependent on antiapoptotic signaling for survival and resistance to death stimuli. Recent mechanistic studies have revealed that increased cellular expression of the E3 ubiquitin-protein ligase X-linked inhibitor of apoptosis (XIAP) impairs TRAIL- and chemotherapy-induced cytotoxicity, promoting survival of cholangiocarcinoma cells. This study was undertaken to determine if pharmacologic antagonism of XIAP protein was sufficient to sensitize cholangiocarcinoma cells to cell death. We employed malignant cholangiocarcinoma cell lines and used embelin to antagonize XIAP protein. Embelin treatment resulted in decreased XIAP protein levels by 8 hours of treatment with maximal effect at 16 hours in KMCH and Mz-ChA-1 cells. Assessment of nuclear morphology demonstrated a concentration-dependent increase in nuclear staining. Interestingly, embelin induced nuclear morphology changes as a single agent, independent of the addition of TNF-related apoptosis inducing ligand (TRAIL). However, caspase activity assays revealed that increasing embelin concentrations resulted in slight inhibition of caspase activity, not activation. In addition, the use of a pan-caspase inhibitor did not prevent nuclear morphology changes. Finally, embelin treatment of cholangiocarcinoma cells did not induce DNA fragmentation or PARP cleavage. Apoptosis does not appear to contribute to the effects of embelin on cholangiocarcinoma cells. Instead, embelin caused inhibition of cell proliferation and cell cycle analysis indicated that embelin increased the number of cells in S and G2/M phase. Our results demonstrate that embelin decreased proliferation in cholangiocarcinoma cell lines. Embelin treatment resulted in decreased XIAP protein expression, but did not induce or enhance apoptosis. Thus, in cholangiocarcinoma cells the mechanism of action of embelin may not be dependent on apoptosis.
登录
查看更多内容
影响因子：
2.9
作者：
KUBISTA, M;AKERMAN, B;NORDEN, B
通讯作者：
NORDEN, B
影响因子：
5.7
作者：
Aird, Katherine M.;Ding, Xiuyun;Devi, Gayathri R.
通讯作者：
Devi, Gayathri R.
影响因子：
64.5
作者：
Du, CY;Fang, M;Wang, XD
通讯作者：
Wang, XD
DOI：
10.1016/j.jss.2010.03.067
发表时间：
2010-10
期刊：
The Journal of surgical research
影响因子：
--
作者：
Clawson KA;Borja-Cacho D;Antonoff MB;Saluja AK;Vickers SM
通讯作者：
Vickers SM
影响因子：
2.9
作者：
BRANDTS, JF;LIN, LN
通讯作者：
LIN, LN