Mitochondrial division inhibitor 1 (mdivi-1) enhances death receptor-mediated apoptosis in human ovarian cancer cells.
Mitochondrial division inhibitor 1 (mdivi-1) enhances death receptor-mediated apoptosis in human ovarian cancer cells.
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DOI：
10.1016/j.bbrc.2014.11.010
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发表时间：
2015-01-02
影响因子：
3.1
通讯作者：
Qian, Wei
中科院分区：
文献类型：
--
作者：
Wang, Jingnan;Hansen, Karyn;Edwards, Robert;Van Houten, Bennett;Qian, Wei
肿瘤坏死因子相关的凋亡诱导配体(TRAIL)是治疗包括卵巢癌在内的多种肿瘤的一种很有前途的靶向治疗方法。然而，肿瘤细胞对TRAIL的固有或获得性耐药限制了TRAIL介导治疗的潜在应用。在本研究中，我们发现线粒体分裂抑制因子-1(MDVI-1)能够增强人卵巢癌细胞对TRAIL、Fas配体和肿瘤坏死因子-α等死亡受体配体的敏感性。重要的是，TRAIL和mdivi-1的组合对未转化的人类细胞没有明显的细胞毒性作用，这表明了一个重要的治疗窗口。我们发现TRAIL和mdivi-1的结合作用需要caspase-8，而不是TRAIL受体的调节。我们进一步证明，mdivi-1和死亡配体的联合作用并不依赖于最初报道的mdivi-1的靶点Drp1，也不依赖于两个重要的促凋亡的Bcl-2家族蛋白Bax和Bak。因此，我们的研究为增强死亡受体配体的凋亡效应提供了一种新的策略，并为以TRAIL为基础的联合治疗卵巢癌提供了新的有效途径。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of a variety of cancers including ovarian cancer. However, the inherent or acquired resistance of tumor cells to TRAIL limits the potential application of TRAIL-mediated therapy. In this study, we identified that mitochondrial division inhibitor-1 (mdivi-1) is able to enhance the sensitivity of human ovarian cancer cells to death receptor ligands including TRAIL, FAS ligands, and TNF-α. Importantly, the combination of TRAIL and mdivi-1 has no apparent cytotoxic effect on non-transformed human cells, indicating a significant therapeutic window. We identified that caspase-8 and not the modulation of TRAIL receptors is required for the combination effect of TRAIL and mdivi-1. We further demonstrated that the enhanced efficacy of combination of mdivi-1 and death ligands is not dependent on the originally reported target of mdivi-1, Drp1, and is also not dependent on the two important pro-apoptotic Bcl-2 family proteins Bax and Bak. Thus, our study presents a novel strategy in enhancing the apoptotic effect of death receptor ligands and provides a new effective TRAIL-based combination approach for treating human ovarian cancer.
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影响因子：
5.6
作者：
Kessler M;Fotopoulou C;Meyer T
通讯作者：
Meyer T
DOI：
10.1083/jcb.200610042
发表时间：
2007-05-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Wasiak S;Zunino R;McBride HM
通讯作者：
McBride HM
影响因子：
12.4
作者：
Ganten, TM;Haas, TL;Walczak, H
通讯作者：
Walczak, H
影响因子：
11.5
作者：
Herzog, TJ
通讯作者：
Herzog, TJ
影响因子：
--
作者：
Lackner LL;Nunnari J
通讯作者：
Nunnari J