Small interfering RNA-mediated silencing of mitochondrial NADP+-dependent isocitrate dehydrogenase enhances the sensitivity of HeLa cells toward tumor necrosis factor-α and anticancer drugs

被引:48
作者
Kil, In Sup [1 ]
Kim, Sung Youl [1 ]
Lee, Sun Joo [1 ]
Park, Jeen-Woo [1 ]
机构
[1] Kyungpook Natl Univ, Coll Nat Sci, Sch Life Sci & Biotechnol, Taegu 702701, South Korea
基金
新加坡国家研究基金会;
关键词
antioxidant enzyme; siRNA; apoptosis; mitochondria; redox status; free radicals;
D O I
10.1016/j.freeradbiomed.2007.07.009
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Tumor necrosis factor-alpha (TNF-alpha) and several anticancer drugs induce the production of reactive oxygen species, which play an important causative role in apoptotic cell death. Recently, we demonstrated that the control of mitochondrial redox balance and the cellular defense against oxidative damage is one of the primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) by supplying NADPH for antioxidant systems. In the present report, we show that silencing of 1DPm expression in HeLa cells greatly enhances apoptosis induced by TNF-alpha and anticancer drugs. Transfection of HeLa cells with an IDPm small interfering RNA (siRNA) markedly decreased activity of IDPm, enhancing the susceptibility of anticancer agent-induced apoptosis reflected by morphological evidence of apoptosis, DNA fragmentation, cellular redox status, mitochondria redox status and function, and the modulation of apoptotic marker proteins. These results indicate that IDPm may play an important role in regulating the apoptosis induced by TNF-alpha and anticancer drugs and the sensitizing effect of IDPm siRNA on the apoptotic cell death of HeLa cells offers the possibility of developing a modifier of cancer chemotherapy. (c) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:1197 / 1207
页数:11
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