Bioenergetic analysis of ovarian cancer cell lines: profiling of histological subtypes and identification of a mitochondria-defective cell line.
Bioenergetic analysis of ovarian cancer cell lines: profiling of histological subtypes and identification of a mitochondria-defective cell line.
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DOI：
10.1371/journal.pone.0098479
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hempel N
中科院分区：
文献类型：
--
作者：
Dier U;Shin DH;Hemachandra LP;Uusitalo LM;Hempel N
上皮性卵巢癌（EOC）是所有妇科癌症中最致命的，并且包括具有特定遗传和组织来源差异的不同组织学亚型。卵巢透明细胞癌（OCCC）占约10%的病例，并被称为应激反应性癌症。OCCC的特征是氧化应激和糖酵解相关基因的表达增加。在本研究中，我们假设生物能量分析可能是唯一区分OCCC从其他EOC组织学亚型。使用细胞外通量分析仪，OCCC系（ES-2，TOV-21-G）显示出高代谢活性，具有高耗氧速率（OCR）和高细胞外酸化速率（ECAR），分别指示增强的线粒体氧化磷酸化和糖酵解速率。高生物能量学特征与细胞系形成锚定非依赖性球体的能力相关。鉴于其高的糖酵解和线粒体活性，OCCC细胞显示出对2-脱氧-D-葡萄糖和鱼藤酮生长抑制的强烈敏感性，尽管这种化学敏感性特征并非仅特异于OCCC细胞。生物能量分析还鉴定了非OCCC细胞系OVCA 420，其具有严重受损的线粒体功能，这是基于低OCR和在应用解偶联剂FCCP后缺乏最大呼吸的刺激。这是伴随着线粒体形态学的变化，指示增强分裂，线粒体分裂蛋白Drp 1的表达增加，线粒体膜电位的损失和依赖糖酵解。重要的是，这种线粒体功能的丧失伴随着OVCA 420细胞无法科普缺氧应激，以及响应1%O2缺氧的稳定HIF-1α的能力受损。这些知识对于计划利用该细胞系进一步研究代谢和缺氧的研究人员来说可能是必要的，并表明改变的线粒体裂变动力学代表了EOCs亚群的表型。
Epithelial ovarian cancer (EOC) is the most lethal of all gynecological cancers, and encompasses distinct histological subtypes that have specific genetic and tissues-of-origin differences. Ovarian clear cell carcinoma (OCCC) represents approximately 10% of cases and has been termed a stress responsive cancer. OCCC is characterized by increased expression of oxidative stress and glycolysis-related genes. In the present study, we hypothesized that bioenergetic profiling might uniquely distinguish OCCC from other EOC histological subtypes. Using an extracellular flux analyzer, OCCC lines (ES-2, TOV-21-G) were shown to be highly metabolically active, with high oxygen consumption rate (OCR) and high extracellular acidification rate (ECAR), indicative of enhanced mitochondrial oxidative phosphorylation and glycolytic rate, respectively. A high bioenergetics profile was associated with the cell lines' ability to form anchorage independent spheroids. Given their high glycolytic and mitochondrial activity, OCCC cells displayed strong sensitivity to 2-deoxy-D-glucose and Rotenone growth inhibition, although this chemosensitivity profile was not specific to only OCCC cells. Bioenergetic profiling also identified a non-OCCC cell line, OVCA420, to have severely compromised mitochondrial function, based on low OCR and a lack of stimulation of maximal respiration following application of the uncoupler FCCP. This was accompanied by mitochondrial morphology changes indicative of enhanced fission, increased expression of the mitochondrial fission protein Drp1, a loss of mitochondrial membrane potential and dependence on glycolysis. Importantly, this loss of mitochondrial function was accompanied by the inability of OVCA420 cells to cope with hypoxic stress, and a compromised ability to stabilize HIF-1α in response to 1% O2 hypoxia. This knowledge may be imperative for researchers planning to utilize this cell line for further studies of metabolism and hypoxia, and suggests that altered mitochondrial fission dynamics represents a phenotype of a subpopulation of EOCs.
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影响因子：
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作者：
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影响因子：
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Brenton, James D.
影响因子：
3.7
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Hill BG;Benavides GA;Lancaster JR Jr;Ballinger S;Dell'Italia L;Jianhua Z;Darley-Usmar VM
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Darley-Usmar VM