Involvement of both intrinsic and extrinsic pathways in IFN-γ-induced apoptosis that are enhanced with cisplatin
Involvement of both intrinsic and extrinsic pathways in IFN-γ-induced apoptosis that are enhanced with cisplatin
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DOI：
10.1016/j.ejca.2005.03.022
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发表时间：
2005-07-01
影响因子：
8.4
通讯作者：
Burke, F
中科院分区：
文献类型：
--
作者：
Barton, C;Davies, D;Burke, F
ifn - γ对卵巢癌细胞系和卵巢癌腹水分离的肿瘤细胞具有直接的抗增殖作用。本研究的目的是进一步阐明其机制。在同步细胞群中检测到ifn - γ介导的细胞周期阻断。caspase依赖性的细胞凋亡也被诱导。当caspase活性被阻断时，ifn - γ的抗增殖作用仅部分降低，表明其在生长抑制和凋亡作用中具有独立的作用。我们已经证明了内在凋亡途径的参与；ifn - γ处理导致线粒体膜去极化，细胞色素c释放到细胞质中，并激活半胱天冬酶9。细胞色素e的释放被一种一般的半胱天冬酶抑制剂阻断，这表明半胱天冬酶在线粒体上游的作用。其中一个候选是caspase 8，它在ifn - γ处理的细胞中也被激活。Bid是一种促凋亡分子，可在caspase 8裂解时介导线粒体膜通透性，其水平也下降，表明这两种途径在ifn - γ诱导的凋亡中存在潜在联系。此外，ifn - γ与顺铂一起发挥更强的抗增殖作用。(c) 2005 Elsevier Ltd版权所有。
IFN-gamma has direct anti-proliferative effects on ovarian cancer cell lines and tumour cells isolated from ovarian cancer ascites. The aim of this study was to further elucidate the mechanisms involved. An IFN-gamma-mediated cell cycle blockade was detectable in synchronised cell populations. Apoptosis, which was caspase dependent, was also induced. When caspase activity was blocked, the anti-proliferative effect of IFN-gamma was only partially reduced indicating independent roles for both growth inhibition and apoptosis in its actions. We have demonstrated involvement of the intrinsic apoptotic pathway; IFN-gamma treatment resulted in mitochondrial membrane depolarisation, cytochrome c release into the cytosol and activation of caspase 9. Cytochrome e release was blocked by the presence of a general caspase inhibitor, suggesting a role for caspases upstream of the mitochondria. One candidate is caspase 8, which was also activated in cells treated with IFN-gamma. Levels of Bid, a pro-apoptotic molecule that can mediate mitochondrial membrane permeabilisation when cleaved by caspase 8, were also decreased and indicated a potential link between these two pathways in IFN-gamma-induced apoptosis. Furthermore, together with cisplatin, IFN-gamma exerted a more powerful anti-proliferative effect. (c) 2005 Elsevier Ltd. All rights reserved.