Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells.
Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells.
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DOI：
10.1371/journal.pone.0071115
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Weiss RH
中科院分区：
文献类型：
--
作者：
Abu Aboud O;Wettersten HI;Weiss RH
肾细胞癌（RCC）是美国第六大常见癌症。虽然RCC是高度转移性的，但转移性RCC患者的治疗选择很少，即使使用最新的靶向治疗，患者的无进展生存期也只有两年。因此，迫切需要这种疾病的新的治疗靶点。基于我们先前的代谢组学研究显示RCC患者和异种移植小鼠材料中过氧化物酶体增殖物激活受体α（PPARα）相关事件的改变，在RCC背景下的当前研究中进一步检查了该途径。PPARα是一种核受体蛋白，作为基因的转录因子发挥作用，包括编码参与能量代谢的酶的基因;虽然据报道，PPARα可调节多种癌症的肿瘤生长，但尚未在RCC中进行评估。一种特异性的PPARα拮抗剂GW 6471可诱导VHL（+）和VHL（−）RCC细胞系（786-O和Caki-1）细胞凋亡和细胞周期停滞在G 0/G1期，并与细胞周期调节蛋白c-Myc、Cyclin D1和CDK 4的衰减相关;通过siRNA方法证实该数据特异于PPARα拮抗作用。有趣的是，当糖酵解被几种方法阻断时，GW 6471的细胞毒性协同增加，表明从糖酵解转换为脂肪酸氧化，并为RCC提供了一种全新的治疗方法。
Renal cell carcinoma (RCC) is the sixth most common cancer in the US. While RCC is highly metastatic, there are few therapeutics options available for patients with metastatic RCC, and progression-free survival of patients even with the newest targeted therapeutics is only up to two years. Thus, novel therapeutic targets for this disease are desperately needed. Based on our previous metabolomics studies showing alteration of peroxisome proliferator-activated receptor α (PPARα) related events in both RCC patient and xenograft mice materials, this pathway was further examined in the current study in the setting of RCC. PPARα is a nuclear receptor protein that functions as a transcription factor for genes including those encoding enzymes involved in energy metabolism; while PPARα has been reported to regulate tumor growth in several cancers, it has not been evaluated in RCC. A specific PPARα antagonist, GW6471, induced both apoptosis and cell cycle arrest at G0/G1 in VHL(+) and VHL(−) RCC cell lines (786-O and Caki-1) associated with attenuation of the cell cycle regulatory proteins c-Myc, Cyclin D1, and CDK4; this data was confirmed as specific to PPARα antagonism by siRNA methods. Interestingly, when glycolysis was blocked by several methods, the cytotoxicity of GW6471 was synergistically increased, suggesting a switch to fatty acid oxidation from glycolysis and providing an entirely novel therapeutic approach for RCC.
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影响因子：
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