Wang Jingnan, Hansen Karyn, Edwards Robert, Van Houten Bennett, Qian Wei
Tsinghua University School of Medicine, Tsinghua University, Haidian District, Beijing 100084, China.
Department of Obstetrics & Gynecology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Biochem Biophys Res Commun. 2015 Jan 2;456(1):7-12. doi: 10.1016/j.bbrc.2014.11.010. Epub 2014 Nov 13.
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.
基于肿瘤坏死因子相关凋亡诱导配体（TRAIL）的策略是一种很有前景的靶向治疗方法，可用于治疗包括卵巢癌在内的多种癌症。然而，肿瘤细胞对TRAIL的固有或获得性耐药限制了TRAIL介导疗法的潜在应用。在本研究中，我们发现线粒体分裂抑制剂-1（mdivi-1）能够增强人卵巢癌细胞对包括TRAIL、FAS配体和TNF-α在内的死亡受体配体的敏感性。重要的是，TRAIL与mdivi-1的联合使用对未转化的人细胞没有明显的细胞毒性作用，表明存在显著的治疗窗口。我们发现，TRAIL与mdivi-1的联合作用需要caspase-8，而不是TRAIL受体的调节。我们进一步证明，mdivi-1与死亡配体联合使用增强的疗效不依赖于最初报道的mdivi-1靶点Drp1，也不依赖于两个重要的促凋亡Bcl-2家族蛋白Bax和Bak。因此，我们的研究提出了一种增强死亡受体配体凋亡效应的新策略，并为治疗人类卵巢癌提供了一种新的基于TRAIL的有效联合方法。
