Primary clear cell renal carcinoma cells display minimal mitochondrial respiratory capacity resulting in pronounced sensitivity to glycolytic inhibition by 3-Bromopyruvate.
Primary clear cell renal carcinoma cells display minimal mitochondrial respiratory capacity resulting in pronounced sensitivity to glycolytic inhibition by 3-Bromopyruvate.
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DOI：
10.1038/cddis.2014.545
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发表时间：
2015-01-08
影响因子：
9
通讯作者：
Johansson ME
中科院分区：
文献类型：
--
作者：
Nilsson H;Lindgren D;Mandahl Forsberg A;Mulder H;Axelson H;Johansson ME
细胞代谢的改变是大多数癌细胞恶性潜能的一个组成部分。早在20世纪30年代，奥托·沃伯格就观察到，肿瘤细胞更好地利用糖酵解和乳酸发酵来产生能量，而不是正常细胞中占主导地位的线粒体氧化磷酸化，这一现象今天被称为沃伯格效应。尽管许多肿瘤类型表现出高度的有氧糖酵解，但它们仍然保留了其他产生能量的代谢途径的活性。一个例外似乎是肾细胞癌的透明细胞变种，ccRCC，除了糖酵解外，大多数其他途径的活性都被证明是减少的。这使得ccRCC成为糖酵解抑制剂治疗该病的一个有前途的候选药物。然而，到目前为止，很少有研究解决这个问题。在这份报告中，我们发现原代人肾小管细胞线粒体呼吸能力显著降低，导致对3-溴丙酮酸(3BrPA)抑制糖酵解的敏感性增强。在已建立的ccRCC细胞系中，这种效应基本上是不存在的，这一发现突显了使用生物学相关模型来寻找新的候选癌症治疗方法的重要性。3BrPA可显著降低原代肾癌细胞的ATP生成，导致细胞死亡。我们的数据表明，糖酵解抑制剂，如3BrPA，已经被证明在体内耐受性良好，应该进一步分析，以便为慢性肾细胞癌患者制定可能的选择性治疗策略。
Changes of cellular metabolism are an integral property of the malignant potential of most cancer cells. Already in the 1930s, Otto Warburg observed that tumor cells preferably utilize glycolysis and lactate fermentation for energy production, rather than the mitochondrial oxidative phosphorylation dominating in normal cells, a phenomenon today known as the Warburg effect. Even though many tumor types display a high degree of aerobic glycolysis, they still retain the activity of other energy-producing metabolic pathways. One exception seems to be the clear cell variant of renal cell carcinoma, ccRCC, where the activity of most other pathways than that of glycolysis has been shown to be reduced. This makes ccRCC a promising candidate for the use of glycolytic inhibitors in treatment of the disease. However, few studies have so far addressed this issue. In this report, we show a strikingly reduced mitochondrial respiratory capacity of primary human ccRCC cells, resulting in enhanced sensitivity to glycolytic inhibition by 3-Bromopyruvate (3BrPA). This effect was largely absent in established ccRCC cell lines, a finding that highlights the importance of using biologically relevant models in the search for new candidate cancer therapies. 3BrPA markedly reduced ATP production in primary ccRCC cells, followed by cell death. Our data suggest that glycolytic inhibitors such as 3BrPA, that has been shown to be well tolerated in vivo, should be further analyzed for the possible development of selective treatment strategies for patients with ccRCC.