Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth
Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth
复制标题
DOI：
10.1158/0008-5472.can-06-4447
复制
发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Thompson, Craig B.
中科院分区：
文献类型：
--
作者：
Buzzai, Monica;Jones, Russell G.;Thompson, Craig B.
使用配对的等基因结肠癌细胞系HCT 116 p53（+/+）和HCT 116 p53（-/-）研究了抗糖尿病药物二甲双胍对肿瘤生长的影响。二甲双胍治疗选择性抑制HCT 116 p53（-/-）异种移植物的肿瘤生长。二甲双胍治疗后，我们检测到p53（-/-）肿瘤切片中的凋亡增加，并且当受到营养剥夺时，p53（-/-）细胞在体外经历凋亡的敏感性增强。二甲双胍在糖尿病治疗中被认为是AIMP活化蛋白激酶（AMPK）的间接激活剂。用AICAR（另一种AMPK激活剂）治疗也显示出选择性抑制体内p53（-/-）肿瘤生长的能力。在两种药物中的任一种存在下，HCT 116 P53（+/+）细胞而不是HCT 116 p53（-/-）细胞激活自噬。当处理非转化的小鼠胚胎成纤维细胞时，观察到类似的p53依赖性自噬诱导。二甲双胍或AICAR治疗也导致p53（+/+）MEFs中脂肪酸β-氧化增强，但在p53（-/-）MEFs中没有。然而，二甲双胍处理的细胞中诱导的幅度显著较低，因为二甲双胍处理也抑制线粒体电子传递。二甲双胍处理的细胞通过以p53依赖的方式增加糖酵解速率来补偿氧化磷酸化的抑制。总之，这些数据表明二甲双胍治疗迫使p53（-/-）细胞无法执行的代谢转换。因此，二甲双胍对p53缺陷细胞具有选择性毒性，并为二甲双胍治疗患者中观察到的肿瘤发生率降低提供了潜在机制。
The effect of the antidiabetic drug metformin on tumor growth was investigated using the paired isogenic colon cancer cell lines HCT116 p53(+/+) and HCT116 p53(-/-) . Treatment with metformin selectively suppressed the tumor growth of HCT116 p53(-/-) xenografts. Following treatment with metformin, we detected increased apoptosis in p53(-/-) tumor sections and an enhanced susceptibility of p53(-/-) cells to undergo apoptosis in vitro when subject to nutrient deprivation. Metformin is proposed to function in diabetes treatment as an indirect activator of AIMP-activated protein kinase (AMPK). Treatment with AICAR, another AMPK activator, also showed a selective ability to inhibit p53(-/-) tumor growth in vivo. In the presence of either of the two drugs, HCT116 P53(+/+) cells, but not HCT116 p53(-/-) cells, activated autophagy. A similar p53-dependent induction of autophagy was observed when nontransformed mouse embryo fibroblasts were treated. Treatment with either metformin or AICAR also led to enhanced fatty acid beta-oxidation in p53(+/+) MEFs but not in p53(-/-) MEFs. However, the magnitude of induction was significantly lower in metformin-treated cells, as metformin treatment also suppressed mitochondrial electron transport. Metformin-treated cells compensated for this suppression of oxidative phosphorylation by increasing their rate of glycolysis in a p53-dependent manner. Together, these data suggest that metformin treatment forces a metabolic conversion that p53(-/-) cells are unable to execute. Thus, metformin is selectively toxic to p53-deficient cells and provides a potential mechanism for the reduced incidence of tumors observed in patients being treated with metformin.