Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer.
Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer.
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DOI：
10.1038/srep19569
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发表时间：
2016-01-22
影响因子：
4.6
通讯作者：
Sambuceti G
中科院分区：
文献类型：
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作者：
Marini C;Bianchi G;Buschiazzo A;Ravera S;Martella R;Bottoni G;Petretto A;Emionite L;Monteverde E;Capitanio S;Inglese E;Fabbi M;Bongioanni F;Garaboldi L;Bruzzi P;Orengo AM;Raffaghello L;Sambuceti G
新出现的证据表明，靶向能量代谢是一种很有前途的抗癌策略。在这里，我们表明，二甲双胍和短期饥饿相结合，显着损害代谢和结肠癌和乳腺癌的生长。二甲双胍通过干扰己糖激酶II活性增强饥饿引起的糖酵解通量受损，如18 F-氟脱氧葡萄糖摄取测量所示。氧化磷酸化通过联合治疗而被相加性地损害：二甲双胍实际上消除了复合物I的功能;饥饿决定了OXPHOS的解偶联状态并放大了呼吸复合物II和IV的活性，从而将大量ATP消耗与活性氧的显著增加相结合。更重要的是，在乳腺癌和结肠癌的实验模型中，联合治疗深刻地损害了癌症的葡萄糖代谢，并且几乎消除了病变的生长。我们的研究结果强烈表明，能量代谢是一个有希望的目标，以减少癌症的进展。
Emerging evidence demonstrates that targeting energy metabolism is a promising strategy to fight cancer. Here we show that combining metformin and short-term starvation markedly impairs metabolism and growth of colon and breast cancer. The impairment in glycolytic flux caused by starvation is enhanced by metformin through its interference with hexokinase II activity, as documented by measurement of 18F-fluorodeoxyglycose uptake. Oxidative phosphorylation is additively compromised by combined treatment: metformin virtually abolishes Complex I function; starvation determines an uncoupled status of OXPHOS and amplifies the activity of respiratory Complexes II and IV thus combining a massive ATP depletion with a significant increase in reactive oxygen species. More importantly, the combined treatment profoundly impairs cancer glucose metabolism and virtually abolishes lesion growth in experimental models of breast and colon carcinoma. Our results strongly suggest that energy metabolism is a promising target to reduce cancer progression.