Abu Aboud Omran, Donohoe Dallas, Bultman Scott, Fitch Mark, Riiff Tim, Hellerstein Marc, Weiss Robert H
Graduate Group in Comparative Pathology, University of California, Davis, California; Division of Nephrology, Department of Internal Medicine, University of California, Davis, California;
Department of Nutrition, University of Tennessee, Knoxville, Tennessee;
Am J Physiol Cell Physiol. 2015 Jun 1;308(11):C890-8. doi: 10.1152/ajpcell.00322.2014. Epub 2015 Mar 25.
Kidney cancer [renal cell carcinoma (RCC)] is the sixth-most-common cancer in the United States, and its incidence is increasing. The current progression-free survival for patients with advanced RCC rarely extends beyond 1-2 yr due to the development of therapeutic resistance. We previously identified peroxisome proliferator-activating receptor-α (PPARα) as a potential therapeutic target for this disease and showed that a specific PPARα antagonist, GW6471, induced apoptosis and cell cycle arrest at G0/G1 in RCC cell lines associated with attenuation of cell cycle regulatory proteins. We now extend that work and show that PPARα inhibition attenuates components of RCC metabolic reprogramming, capitalizing on the Warburg effect. The specific PPARα inhibitor GW6471, as well as a siRNA specific to PPARα, attenuates the enhanced fatty acid oxidation and oxidative phosphorylation associated with glycolysis inhibition, and PPARα antagonism also blocks the enhanced glycolysis that has been observed in RCC cells; this effect did not occur in normal human kidney epithelial cells. Such cell type-specific inhibition of glycolysis corresponds with changes in protein levels of the oncogene c-Myc and has promising clinical implications. Furthermore, we show that treatment with GW6471 results in RCC tumor growth attenuation in a xenograft mouse model, with minimal obvious toxicity, a finding associated with the expected on-target effects on c-Myc. These studies demonstrate that several pivotal cancer-relevant metabolic pathways are inhibited by PPARα antagonism. Our data support the concept that targeting PPARα, with or without concurrent inhibition of glycolysis, is a potential novel and effective therapeutic approach for RCC that targets metabolic reprogramming in this tumor.
肾癌[肾细胞癌（RCC）]是美国第六大常见癌症，且其发病率正在上升。由于治疗耐药性的出现，晚期RCC患者目前的无进展生存期很少能超过1 - 2年。我们之前将过氧化物酶体增殖物激活受体-α（PPARα）鉴定为该疾病的一个潜在治疗靶点，并表明一种特异性PPARα拮抗剂GW6471可诱导RCC细胞系凋亡并使细胞周期停滞在G0/G1期，这与细胞周期调节蛋白的减弱有关。我们现在扩展这项工作，并表明PPARα抑制可减弱RCC代谢重编程的组成部分，利用了瓦伯格效应。特异性PPARα抑制剂GW6471以及针对PPARα的小干扰RNA（siRNA）可减弱与糖酵解抑制相关的增强的脂肪酸氧化和氧化磷酸化，并且PPARα拮抗作用还可阻断在RCC细胞中观察到的增强的糖酵解；这种效应在正常人肾上皮细胞中未出现。这种细胞类型特异性的糖酵解抑制与癌基因c-Myc蛋白水平的变化相对应，并具有有前景的临床意义。此外，我们表明用GW6471治疗可使异种移植小鼠模型中的RCC肿瘤生长减缓，且毒性极小，这一发现与对c-Myc的预期靶向效应相关。这些研究表明，PPARα拮抗作用可抑制几种关键的与癌症相关的代谢途径。我们的数据支持这样一种概念，即靶向PPARα，无论是否同时抑制糖酵解，都是一种针对RCC的潜在新型有效治疗方法，该方法靶向此肿瘤中的代谢重编程。
