O'Brien Andrew J, Villani Linda A, Broadfield Lindsay A, Houde Vanessa P, Galic Sandra, Blandino Giovanni, Kemp Bruce E, Tsakiridis Theodoros, Muti Paola, Steinberg Gregory R
Departments of Medicine, McMaster University, 1280 Main St. West, Hamilton, Ontario, Canada L8K 4P1.
St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065, Australia.
Biochem J. 2015 Jul 15;469(2):177-87. doi: 10.1042/BJ20150122. Epub 2015 May 5.
Aspirin, the pro-drug of salicylate, is associated with reduced incidence of death from cancers of the colon, lung and prostate and is commonly prescribed in combination with metformin in individuals with type 2 diabetes. Salicylate activates the AMP-activated protein kinase (AMPK) by binding at the A-769662 drug binding site on the AMPK β1-subunit, a mechanism that is distinct from metformin which disrupts the adenylate charge of the cell. A hallmark of many cancers is high rates of fatty acid synthesis and AMPK inhibits this pathway through phosphorylation of acetyl-CoA carboxylase (ACC). It is currently unknown whether targeting the AMPK-ACC-lipogenic pathway using salicylate and/or metformin may be effective for inhibiting cancer cell survival. Salicylate suppresses clonogenic survival of prostate and lung cancer cells at therapeutic concentrations achievable following the ingestion of aspirin (<1.0 mM); effects not observed in prostate (PNT1A) and lung (MRC-5) epithelial cell lines. Salicylate concentrations of 1 mM increased the phosphorylation of ACC and suppressed de novo lipogenesis and these effects were enhanced with the addition of clinical concentrations of metformin (100 μM) and eliminated in mouse embryonic fibroblasts (MEFs) deficient in AMPK β1. Supplementation of media with fatty acids and/or cholesterol reverses the suppressive effects of salicylate and metformin on cell survival indicating the inhibition of de novo lipogenesis is probably important. Pre-clinical studies evaluating the use of salicylate based drugs alone and in combination with metformin to inhibit de novo lipogenesis and the survival of prostate and lung cancers are warranted.
阿司匹林是水杨酸的前体药物，与降低结肠癌、肺癌和前列腺癌的死亡率相关，常用于2型糖尿病患者，与二甲双胍联合使用。水杨酸通过结合在AMPKβ1亚基上的A-769662药物结合位点来激活AMP激活的蛋白激酶（AMPK），这一机制不同于二甲双胍，二甲双胍是通过破坏细胞的腺苷酸电荷来发挥作用。许多癌症的一个标志是脂肪酸合成率高，而AMPK通过磷酸化乙酰辅酶A羧化酶（ACC）来抑制这一途径。目前尚不清楚使用水杨酸和/或二甲双胍靶向AMPK-ACC-脂肪生成途径是否对抑制癌细胞存活有效。在摄入阿司匹林后可达到的治疗浓度（<1.0 mM）下，水杨酸可抑制前列腺癌和肺癌细胞的克隆形成存活；在前列腺（PNT1A）和肺（MRC-5）上皮细胞系中未观察到这种作用。1 mM的水杨酸浓度增加了ACC的磷酸化并抑制了从头脂肪生成，加入临床浓度的二甲双胍（100 μM）可增强这些作用，而在缺乏AMPKβ1的小鼠胚胎成纤维细胞（MEF）中则消除了这些作用。在培养基中添加脂肪酸和/或胆固醇可逆转水杨酸和二甲双胍对细胞存活的抑制作用，这表明抑制从头脂肪生成可能很重要。有必要进行临床前研究，评估单独使用基于水杨酸的药物以及与二甲双胍联合使用，以抑制前列腺癌和肺癌的从头脂肪生成及存活情况。
