Nilsson H, Lindgren D, Mandahl Forsberg A, Mulder H, Axelson H, Johansson M E
Department of Laboratory Medicine Malmö, Center for Molecular Pathology, Lund University, Skåne University Hospital, Malmö, Sweden.
Department of Laboratory Medicine Lund, Division of Translational Cancer Research, Lund University, Lund, Sweden.
Cell Death Dis. 2015 Jan 8;6(1):e1585. doi: 10.1038/cddis.2014.545.
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.
细胞代谢变化是大多数癌细胞恶性潜能的一个固有特性。早在20世纪30年代，奥托·瓦尔堡就观察到肿瘤细胞更倾向于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，这种现象如今被称为瓦尔堡效应。尽管许多肿瘤类型都表现出高度的有氧糖酵解，但它们仍然保留着其他产能量代谢途径的活性。肾细胞癌的透明细胞变体（ccRCC）似乎是个例外，在ccRCC中，除糖酵解途径外，大多数其他途径的活性都已被证明有所降低。这使得ccRCC成为使用糖酵解抑制剂治疗该疾病的一个有前景的候选对象。然而，到目前为止，很少有研究涉及这个问题。在本报告中，我们展示了原代人ccRCC细胞的线粒体呼吸能力显著降低，导致其对3-溴丙酮酸（3BrPA）的糖酵解抑制作用增强。这种效应在已建立的ccRCC细胞系中基本不存在，这一发现凸显了在寻找新的候选癌症治疗方法时使用生物学相关模型的重要性。3BrPA显著降低了原代ccRCC细胞中的ATP生成，随后导致细胞死亡。我们的数据表明，像3BrPA这样已被证明在体内耐受性良好的糖酵解抑制剂，应该进一步分析其用于为ccRCC患者开发选择性治疗策略的可能性。
