阿司匹林抑制mTOR信号，激活amp激活的蛋白激酶，诱导结直肠癌细胞自噬。
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Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG
阿司匹林抑制mTOR信号，激活amp激活的蛋白激酶，诱导结直肠癌细胞自噬。
胃肠病学杂志，2012;142(7):1504- 15e3。doi: 10.1053 / j.gastro.2012.02.050。Epub 2012年3月6日
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22406476 (PubMed视图］
- 摘要
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背景与目的:阿司匹林降低结直肠癌(CRC)发病率和死亡率的机制尚不清楚。癌细胞通过调节增殖的雷帕霉素(mTOR)的机制靶点信号传导存在缺陷。我们研究了阿司匹林是否影响结直肠癌细胞中腺苷单磷酸活化蛋白激酶(AMPK)和mTOR信号传导。方法:采用免疫印迹法检测阿司匹林对结直肠癌细胞mTOR信号、核糖体蛋白S6、S6激酶1 (S6K1)、真核翻译起始因子4E结合蛋白1 (4E- bp1)的影响。测定AMPK的磷酸化水平;在CRC细胞和AMPK(alpha1/alpha2-/-)小鼠胚胎成纤维细胞中使用小干扰RNA (siRNA)检测AMPKalpha缺失对阿司匹林诱导mTOR效应的影响。LC3和ULK1作为自噬的标志物。我们分析了服用600毫克阿司匹林的患者的直肠粘膜样本，每天一次，持续1周。结果:阿司匹林通过抑制mTOR效应物S6K1和4E-BP1降低CRC细胞中的mTOR信号。阿司匹林改变CRC细胞的核苷酸比率并激活AMPK。 mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. Aspirin induced autophagy, a feature of mTOR inhibition. Aspirin and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: Aspirin is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC.