Possible endocannabinoid control of colorectal cancer growth
Possible endocannabinoid control of colorectal cancer growth
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DOI：
10.1016/s0016-5085(03)00881-3
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发表时间：
2003-09-01
期刊：
影响因子：
29.4
通讯作者：
Di Marzo, V
中科院分区：
文献类型：
--
作者：
Ligresti, A;Bisogno, T;Di Marzo, V
背景和目的：内源性大麻素 anandamide 和 2-arachidonoylglycerol (2-AG) 通过作用于大麻素受体 (CBR) 抑制癌细胞增殖。我们研究了（1）结直肠癌（CRC）、腺瘤性息肉和邻近健康粘膜中内源性大麻素、大麻素 CB1 和 CB2 受体以及脂肪酸酰胺水解酶（FAAH，催化内源性大麻素水解）的水平； (2) 内源性大麻素及其失活抑制剂对人结直肠癌细胞增殖的影响。方法：通过结肠镜检查期间活检从 21 名患者身上获取组织。通过液相色谱-质谱法（LC-MS）测量内源性大麻素。通过 RT-PCR 和 Western 免疫印迹分析 CB1、CB2 和 FAAH 表达。 CRC 细胞系（CaCo-2 和 DLD-1）用于测试抗增殖作用。结果：分析的所有组织和细胞均含有大麻素、2-AG、CBR 和 FAAH。腺瘤和结直肠癌中内源性大麻素的水平比正常粘膜高 3 倍和 2 倍。 Anandamide、2-AG 和 CBR 激动剂 HU-210 有效抑制 CaCo-2 细胞增殖。该效应可被 CB1 拮抗剂 SR141716A 阻断，但不能被 CB2 拮抗剂 SR144528 阻断，并且可被 CB1 选择性激动剂模仿，但不能被 CB2 选择性激动剂模仿。在 DLD-1 细胞中，均为 CB1。 CB2受体介导增殖抑制。内源性大麻素失活抑制剂可增强 CaCo-2 细胞内源性大麻素水平并阻止细胞增殖，这种作用可被 SR141716A 拮抗。 CaCo-2 细胞分化为非侵袭性细胞导致 FAAH 表达增加、内源性大麻素水平降低且对大麻素无反应。结论：转化的结肠粘膜细胞中内源性大麻素水平升高，可能是通过 CBR 抵消增殖。内源性大麻素失活抑制剂可能被证明是有用的抗癌剂。
Background & Aims: The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) inhibit cancer cell proliferation by acting at cannabinoid receptors (CBRs). We studied (1) the levels of endocannabinoids, cannabinoid CB1 and CB2 receptors, and fatty acid amide hydrolase (FAAH, which catalyzes endocannabinoid hydrolysis) in colorectal carcinomas (CRC), adenomatous polyps, and neighboring healthy mucosa; and (2) the effects of endocannabinoids, and of inhibitors of their inactivation, on human CRC cell proliferation. Methods: Tissues were obtained from 21 patients by biopsy during colonoscopy. Endocannabinoids were measured by liquid chromatography-mass spectrometry (LC-MS). CB1, CB2, and FAAH expression were analyzed by RT-PCR and Western immunoblotting. CRC cell lines (CaCo-2 and DLD-1) were used to test antiproliferative effects. Results: All tissues and cells analyzed contain anandamide, 2-AG, CBRs, and FAAH. The levels of the endocannabinoids are 3- and 2-fold higher in adenomas and CRCs than normal mucosa. Anandamide, 2-AG, and the CBR agonist HU-210 potently inhibit CaCo-2 cell proliferation. This effect is blocked by the CB1 antagonist SR141716A, but not by the CB2 antagonist SR144528, and is mimicked by CB1-selective, but not CB2-selective, agonists. In DLD-1 cells, both CB1. and CB2 receptors mediate inhibition of proliferation. Inhibitors of endocannabinold inactivation enhance CaCo-2 cell endocannabinoid levels and block cell proliferation, this effect being antagonized by SR141716A. CaCo-2 cell differentiation into noninvasive cells results in increased FAAH expression, lower endocannabinoid levels, and no responsiveness to cannabinoids. Conclusions: Endocannabinoid levels are enhanced in transformed colon mucosa cells possibly to counteract proliferation via CBRs. Inhibitors of endocannabinoid inactivation may prove useful anticancer agents.