阿司匹林抑制mTOR信号通路，激活amp活化蛋白激酶，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信号通路，激活amp活化蛋白激酶，诱导结直肠癌细胞自噬。
消化病学。2012 Jun;142(7):1504-15.e3。doi: 10.1053 / j.gastro.2012.02.050。Epub 2012 3月6日。
- PubMed ID
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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)的发病率和死亡率的机制尚不清楚。癌细胞通过雷帕霉素的机制靶点(mTOR)的信号传递存在缺陷，该靶点调节增殖。我们研究了阿司匹林是否影响CRC细胞中腺苷单磷酸活化蛋白激酶(AMPK)和mTOR信号通路。方法:通过免疫印迹法检测阿司匹林对CRC细胞中mTOR信号通路、核糖体蛋白S6、S6激酶1 (S6K1)和真核翻译起始因子4E结合蛋白1 (4E- bp1)的影响。检测AMPK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)确定AMPKalpha缺失对阿司匹林诱导的mTOR效应的影响。LC3和ULK1作为自噬标志物。我们分析了给予600 mg阿司匹林患者的直肠黏膜样本，每天1次，持续1周。结果:阿司匹林通过抑制mTOR效应子S6K1和4E-BP1来降低CRC细胞中的mTOR信号。阿司匹林改变了CRC细胞的核苷酸比率并激活了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.