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Characterization of cyclooxygenase-2 acetylation and prostanoid inhibition by aspirin in cellular systems

机译：阿司匹林在细胞系统中阿司匹林环氧化酶-2乙酰化和前列腺抑制的表征

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摘要

The most recognized mechanism of aspirin (acetylsalicylic acid, ASA) action, at therapeutic dosing, is the inhibition of prostanoid biosynthesis through the acetylation of cyclooxygenase (COX)-isozymes (COX-1 at serine-529 and COX-2 at serine-516). Whether aspirin, also when given at the low-doses recommended for cardiovascular prevention, reduces the risk of colorectal cancer by affecting COX-2 activity in colorectal adenomatous lesions is still debated. We aimed to develop a direct biomarker of aspirin action on COX-2 by assessing the extent of acetylation of COX-2 at serine-516 using the AQUA strategy, enabling absolute protein quantitation by liquid chromatography-mass spectrometry. We compared the extent of acetylation and the inhibition of prostanoid biosynthesis by ASA using human recombinant COX-2 (hu-COX-2), the human colon cancer cell line HCA-7, isolated human monocytes stimulated with LPS (lipopolysaccharide) or human intestinal epithelial cells stimulated with interleukin (IL)-1 beta. Hu-COX-2 exposed in vitro to an excess of ASA was acetylated by approximately 40-50% associated with the inhibition of COX-2 activity by 80-90%. In the three cell-types expressing COX-2, the extent of COX-2 acetylation and reduction of prostaglandin (PG) E-2 biosynthesis by ASA was concentration-dependent with comparable EC50 values (in the low mu M range). The maximal % acetylation of COX-2 averaged 80%, at ASA 1000 mu M, and was associated with a virtually complete reduction of PGE(2) biosynthesis (97%). In conclusion, we have developed a proteomic assay to evaluate the extent of acetylation of COX-2 at serine-516 by aspirin; its use in clinical studies will allow clarifying the mechanism of action of aspirin as anticancer agent.
机译：在治疗剂量下，阿司匹林（乙酰胱氨酸，ASA）作用的最识别的机制是通过环氧氧酶（COX） - 苏酶（COX-1在丝氨酸-516的丝氨酸-529和COX-2中的乙酰-5和COX-2的乙酰丙烯化生物合成的抑制）。无论是阿司匹林，也是在推荐用于心血管预防的低剂量上给药时，通过影响结肠直肠腺瘤病变的COX-2活性降低结直肠癌的风险仍然讨论。我们旨在通过使用AQUA策略评估丝氨酸-516在丝氨酸-516的乙酰化的程度，通过液相色谱 - 质谱，通过评估COX-2的乙酰化的程度来在COX-2上进行Aspirin作用的直接生物标志物。通过液相色谱 - 质谱，使绝对蛋白质定量。通过使用人重组COX-2（HU-COX-2），用LPS（脂多糖）或人肠道刺激的人结肠癌细胞系HCA-7，对乙酰化和抑制前列腺化生物合成的程度和对前列腺蛋白生物合成的程度和抑制前列腺化生物合成的程度。用白细胞介素（IL）-1β刺激的上皮细胞。在体外暴露于过量的Hu-Cox-2将乙酰化约40-50％与抑制COX-2活性的抑制率为80-90％。在表达COX-2的三种细胞类型中，ASA的COX-2乙酰化和前列腺素（PG）E-2生物合成的降低的程度依赖于相当的EC 50值（在低MU M范围内）。 Cox-2的最大丙基化乙酰化平均为80％，ASA1000μm，并且与PGE（2）生物合成的几乎完全减少相关（97％）。总之，我们开发了蛋白质组学测定，以评估丝氨酸-516的COX-2乙酰化的程度;其在临床研究中的使用将允许澄清阿司匹林作为抗癌剂的作用机制。

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