Tytgat Institute for Liver & Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
Gut. 2012 Dec;61(12):1708-15. doi: 10.1136/gutjnl-2011-301626. Epub 2011 Dec 20.
5-Aminosalicylic acid (5-ASA) may protect against the development of inflammation-associated colorectal cancer. In vitro data suggest that, in colorectal cancer cells, 5-ASA induces cell cycle arrest, but the molecular mechanism leading to this arrest remains to be determined.
To dissect the signal transduction events that lead to 5-ASA mediated inhibition of proliferation of colorectal cancer cells, focusing on mammalian target of rapamycin (mTOR), a regulator of cell cycle progression.
The influence of 5-ASA on mTOR signalling was examined in a panel of colorectal cancer cell lines. The effects of 5-ASA on the pathways that control mTOR activity were studied in detail in two different colorectal cancer cell lines, using western blot, siRNA, a phospholipase D (PLD) activity assay, proliferation assays and cell cycle analysis. The phosphorylation status of mTOR and its downstream target, ribosomal protein S6, was studied in colorectal cancers before and after topical 5-ASA treatment.
Treatment of colorectal cancer with 5-ASA inhibited mTOR signalling in vitro and in vivo. 5-ASA had no effect on any of the pathways that regulate the activity of the tuberous sclerosis complex in colorectal cancer cells. Both proliferation and mTOR activity depended on PLD, an enzyme that generates phosphatidic acid (PA). 5-ASA treatment inhibited PLD activity and proliferation; these effects could be rescued with exogenous PA.
5-ASA interferes with proliferation of colorectal cancer cells via inhibition of PLD-dependent generation of PA and loss of mTOR signalling.
5-氨基水杨酸（5-ASA）可能有助于预防炎症相关的结直肠癌。体外数据表明，在结直肠癌细胞中，5-ASA 诱导细胞周期停滞，但导致这种停滞的分子机制仍有待确定。
剖析导致 5-ASA 抑制结直肠癌细胞增殖的信号转导事件，重点关注哺乳动物雷帕霉素靶蛋白（mTOR），这是细胞周期进程的调节剂。
在一系列结直肠癌细胞系中检查 5-ASA 对 mTOR 信号的影响。使用 Western blot、siRNA、磷脂酶 D（PLD）活性测定、增殖测定和细胞周期分析，详细研究了 5-ASA 对控制 mTOR 活性的途径在两种不同的结直肠癌细胞系中的作用。研究了结直肠癌患者在局部应用 5-ASA 前后 mTOR 及其下游靶标核糖体蛋白 S6 的磷酸化状态。
5-ASA 处理结直肠癌细胞在体外和体内均抑制 mTOR 信号。5-ASA 对调节结直肠癌细胞中结节性硬化复合物活性的任何途径均无影响。增殖和 mTOR 活性均依赖于 PLD，PLD 可产生磷脂酸（PA）。5-ASA 处理抑制了 PLD 活性和增殖；这些作用可以通过外源性 PA 得到挽救。
5-ASA 通过抑制 PLD 依赖性生成 PA 和丧失 mTOR 信号来干扰结直肠癌细胞的增殖。
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