The glucose and lipid metabolism reprogramming is grade-dependent in clear cell renal cell carcinoma primary cultures and is targetable to modulate cell viability and proliferation.
The glucose and lipid metabolism reprogramming is grade-dependent in clear cell renal cell carcinoma primary cultures and is targetable to modulate cell viability and proliferation.
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DOI：
10.18632/oncotarget.23056
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发表时间：
2017-12-26
期刊：
影响因子：
--
通讯作者：
Perego RA
中科院分区：
文献类型：
--
作者：
Bianchi C;Meregalli C;Bombelli S;Di Stefano V;Salerno F;Torsello B;De Marco S;Bovo G;Cifola I;Mangano E;Battaglia C;Strada G;Lucarelli G;Weiss RH;Perego RA
尽管有新的生物靶向治疗，透明细胞肾细胞癌（ccRCC）的预后仍很差。肿瘤侵袭性和生存率低可能与诊断时的肿瘤分级和复杂的代谢改变相关，也涉及葡萄糖和脂质代谢。然而，目前没有等级特异性代谢疗法解决这些改变。在这里，我们使用来自低级别和高级别ccRCC的原代细胞培养物来研究用2-脱氧-D-葡萄糖（2DG）特异性抑制糖酵解或用依托莫西酯特异性抑制脂肪酸氧化对能量状态和降低的吡啶核苷酸水平以及对活力和增殖的影响。我们的原代培养物保留了脂质和糖原储存以及有氧糖酵解的组织等级依赖性调节（瓦尔堡效应）。2DG影响高级别ccRCC培养物的乳酸产生、能量状态和降低的吡啶核苷酸水平，但仅影响低级别ccRCC培养物的能量状态。相反，Etomoxir影响高级培养物中的能量状态，并降低低级培养物中的吡啶核苷酸水平。分别通过ATP和还原3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑（MTT）染料定量评价能量状态和还原吡啶核苷酸水平。2DG处理损害了低级别ccRCC和正常皮质培养物的细胞增殖和活力，而依托莫西仅在高级别ccRCC培养物中显示出细胞抑制和细胞毒性作用。我们的数据表明，在ccRCC中，瓦尔堡效应是一个等级依赖性特征，并且脂肪酸氧化可以被激活以满足不同等级依赖性代谢需求。还强调了ccRCC中可能的等级依赖性代谢治疗方法。
Clear cell renal cell carcinoma (ccRCC) has a poor prognosis despite novel biological targeted therapies. Tumor aggressiveness and poor survival may correlate with tumor grade at diagnosis and with complex metabolic alterations, also involving glucose and lipid metabolism. However, currently no grade-specific metabolic therapy addresses these alterations. Here we used primary cell cultures from ccRCC of low- and high-grade to investigate the effect on energy state and reduced pyridine nucleotide level, and on viability and proliferation, of specific inhibition of glycolysis with 2-deoxy-D-glucose (2DG), or fatty acid oxidation with Etomoxir. Our primary cultures retained the tissue grade-dependent modulation of lipid and glycogen storage and aerobic glycolysis (Warburg effect). 2DG affected lactate production, energy state and reduced pyridine nucleotide level in high-grade ccRCC cultures, but the energy state only in low-grade. Rather, Etomoxir affected energy state in high-grade and reduced pyridine nucleotide level in low-grade cultures. Energy state and reduced pyridine nucleotide level were evaluated by ATP and reduced 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) dye quantification, respectively. 2DG treatment impaired cell proliferation and viability of low-grade ccRCC and normal cortex cultures, whereas Etomoxir showed a cytostatic and cytotoxic effect only in high-grade ccRCC cultures. Our data indicate that in ccRCC the Warburg effect is a grade-dependent feature, and fatty acid oxidation can be activated for different grade-dependent metabolic needs. A possible grade-dependent metabolic therapeutic approach in ccRCC is also highlighted.
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