Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine
Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine
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DOI：
10.1016/j.bbamcr.2012.06.007
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发表时间：
2012-10-01
影响因子：
5.1
通讯作者：
Donadelli, Massimo
中科院分区：
文献类型：
--
作者：
Dalla Pozza, Elisa;Fiorini, Claudia;Donadelli, Massimo
癌细胞表现出比正常细胞更高的内源性组成性氧化应激，这使得肿瘤更容易受到活性氧（ROS）产生的影响。线粒体解偶联蛋白2 （UCP2）可以通过增加质子流入线粒体基质，减少电子泄漏和线粒体超氧化物的产生来减轻氧化应激。在这里，我们证明了化学解偶联剂或UCP2过表达强烈地减少了抗癌药物吉西他滨（GEM）诱导的线粒体超氧化物，并保护癌细胞免受GEM诱导的凋亡。此外，我们发现GEM IC50值与内源性UCP2 mRNA水平有很好的相关性，这表明线粒体解偶联在GEM抗性中起关键作用。有趣的是，GEM处理刺激UCP2 mRNA表达，这表明线粒体解偶联也可能在GEM获得性耐药中发挥作用。相反，通过genipin抑制UCP2或沉默UCP2 mRNA，可以强烈增强gem诱导的线粒体超氧化物生成和凋亡，协同抑制癌细胞增殖。这些事件通过加入自由基清除剂n -乙酰-t-半胱氨酸或MnSOD的过度表达而显著减少，证明了氧化应激的关键作用。正常的原代成纤维细胞对GEM/genipin组合的敏感性要低得多。我们的研究结果首次证明UCP2在癌细胞对GEM的耐药性中发挥作用，支持基于UCP2抑制与GEM治疗相关的抗癌治疗的发展。(C) 2012 Elsevier B.V.版权所有
Cancer cells exhibit an endogenous constitutive oxidative stress higher than that of normal cells, which renders tumours vulnerable to further reactive oxygen species (ROS) production. Mitochondrial uncoupling protein 2 (UCP2) can mitigate oxidative stress by increasing the influx of protons into the mitochondrial matrix and reducing electron leakage and mitochondrial superoxide generation. Here, we demonstrate that chemical uncouplers or UCP2 over-expression strongly decrease mitochondrial superoxide induction by the anticancer drug gemcitabine (GEM) and protect cancer cells from GEM-induced apoptosis. Moreover, we show that GEM IC50 values well correlate with the endogenous level of UCP2 mRNA, suggesting a critical role for mitochondrial uncoupling in GEM resistance. Interestingly, GEM treatment stimulates UCP2 mRNA expression suggesting that mitochondrial uncoupling could have a role also in the acquired resistance to GEM. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing strongly enhances GEM-induced mitochondrial superoxide generation and apoptosis, synergistically inhibiting cancer cell proliferation. These events are significantly reduced by the addition of the radical scavenger N-acetyl-t-cysteine or MnSOD over-expression, demonstrating a critical role of the oxidative stress. Normal primary fibroblasts are much less sensitive to GEM/genipin combination. Our results demonstrate for the first time that UCP2 has a role in cancer cell resistance to GEM supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to GEM treatment. (C) 2012 Elsevier B.V. All rights reserved.