Does Scavenging of Mitochondrial Superoxide Attenuate Cancer Prosurvival Signaling Pathways?
Does Scavenging of Mitochondrial Superoxide Attenuate Cancer Prosurvival Signaling Pathways?
复制标题
DOI：
10.1089/ars.2013.5185
复制
发表时间：
2013-08-01
影响因子：
6.6
通讯作者：
Dikalov, Sergey I.
中科院分区：
文献类型：
--
作者：
Nazarewicz, Rafal R.;Dikalova, Anna;Dikalov, Sergey I.
以前有人认为，线粒体超氧化物歧化酶（SOD）的过度表达减弱了癌症的发展;然而，确切的机制仍不清楚。在这项工作中，我们研究了靶向超氧化物清除剂（2-（2，2，6，6-四甲基哌啶-1-氧基-4-氨基）-2-氧代乙基）三苯基氯化鏻（mitoTEMPO）对B16-F0小鼠黑色素瘤细胞和裸鼠人黑色素瘤模型中肿瘤生长的直接影响。我们发现，清除线粒体超氧化物抑制细胞生长，降低生存能力，并诱导黑色素瘤细胞凋亡，但不影响非恶性皮肤成纤维细胞。减少线粒体超氧化物抑制氧化还原依赖性Akt，恢复线粒体丙酮酸脱氢酶的活性，并降低癌细胞中HIF 1-α和乳酸脱氢酶的表达。在mitoTEMPO处理的黑素瘤细胞中抑制糖酵解导致细胞腺苷-5 '-三磷酸的显著下降并诱导细胞死亡。体内mitoTEMPO治疗有效地抑制了人黑素瘤小鼠模型中建立的肿瘤的生长。因此，我们的数据导致的假设，清除线粒体超氧化物选择性抑制氧化还原敏感的生存和代谢途径，导致癌细胞死亡。与现有的抗癌疗法相比，线粒体超氧化物的抑制可能代表了一种新的特异性抗癌疗法，具有降低的细胞毒性副作用。
It has been previously suggested that overexpression of mitochondrial superoxide dismutase (SOD) attenuates cancer development; however, the exact mechanism remains unclear. In this work, we have studied the direct effect of the mitochondria-targeted superoxide scavenger, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (mitoTEMPO), on B16-F0 mouse melanoma cells and tumor growth in a nude mouse model of human melanoma. We show that scavenging of mitochondrial superoxide inhibited cell growth, reduced viability, and induced apoptosis in melanoma cells, but did not affect nonmalignant skin fibroblasts. Diminished mitochondrial superoxide inhibited redox-dependent Akt, restored activity of mitochondrial pyruvate dehydrogenase, and reduced HIF1-alpha and lactate dehydrogenase expression in cancer cells. Suppression of glycolysis in mitoTEMPO-treated melanoma cells resulted in a significant drop of cellular adenosine-5'-triphosphate and induced cell death. In vivo mitoTEMPO treatment effectively suppressed growth of established tumor in the mouse model of human melanoma. Therefore, our data lead to the hypothesis that scavenging of mitochondrial superoxide selectively inhibits redox-sensitive survival and metabolic pathways, resulting in cancer cell death. In contrast to existing anticancer therapies, inhibition of mitochondrial superoxide may represent a novel specific anticancer treatment with reduced cytotoxic side effects.