Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth
Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth
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DOI：
10.1096/fj.01-0320fje
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发表时间：
2001-10-01
期刊：
影响因子：
4.8
通讯作者：
Di Marzo, V
中科院分区：
文献类型：
--
作者：
Bifulco, M;Laezza, C;Di Marzo, V
我们研究了 2-甲基-花生四烯基-2'-氟-乙酰胺 (Met-F-AEA)（内源性大麻素 anandamide 的稳定类似物）对 K-ras 癌基因转化的大鼠甲状腺上皮细胞系 (FRTL-5) 以及源自这些细胞的上皮肿瘤的影响。在裸鼠异种移植模型中评估了 Met-F-AEA 的体内效应，其中皮下植入 K-ras 转化 (KiMol) 细胞。 Met-F-AEA（0.5 mg/kg/剂量）诱导肿瘤体积急剧减小。这种作用被 CB1 受体拮抗剂 SR141716A（0.7 mg/kg/剂量）抑制，并伴随着 K-ras 活性的强烈降低。因此，KiMol细胞和肿瘤表达CB1受体。 Met-F-AEA抑制KiMol细胞的体外增殖和向S期的转变（IC50约5μM），并降低K-ras活性；这些作用被 SR141716A 拮抗。 Met-F-AEA 在未转化的 FRTL-5 细胞中的细胞抑制作用明显小于 KiMol 细胞中的细胞抑制作用。 Met-F-AEA处理对KiMol和FRTL-5细胞中CB1受体的表达产生相反的影响，在前一种情况下强烈上调，而在非转化细胞中抑制。数据表明：1）Met-F-AEA通过CB1大麻素受体抑制体内ras癌基因依赖性肿瘤生长； 2) FRTL-5 细胞对内源性大麻素的反应取决于它们是否被 K-ras 转化。
We investigated the effect of 2-methyl-arachidonyl-2'-fluoro-ethylamide (Met-F-AEA), a stable analog of the endocannabinoid anandamide, on a rat thyroid epithelial cell line (FRTL-5) transformed by the K-ras oncogene, and on epithelial tumors derived from these cells. Met-F-AEA effect in vivo was evaluated in a nude mouse xenograft model, where K-ras-transformed (KiMol) cells were implanted subcutaneously. Met-F-AEA (0.5 mg/kg/dose) induced a drastic reduction in tumor volume. This effect was inhibited by the CB1 receptor antagonist SR141716A (0.7 mg/kg/dose) and was accompanied by a strong reduction of K-ras activity. Accordingly, KiMol cells and tumors express CB1 receptors. Met-F-AEA inhibited (IC50 similar to5 muM) the proliferation in vitro and the transition to the S phase of KiMol cells and it reduced K-ras activity; these effects were antagonized by SR141716A. Met-F-AEA cytostatic action was significantly smaller in nontransformed FRTL-5 cells than in KiMol cells. Met-F-AEA treatment exerted opposite effects on the expression of CB1 receptors in KiMol and FRTL-5 cells, with a strong up-regulation in the former case and a suppression in nontransformed cells. The data suggest that: 1) Met-F-AEA inhibits ras oncogene-dependent tumor growth in vivo through CB1 cannabinoid receptors; and 2) responsiveness of FRTL-5 cells to endocannabinoids depends on whether or not they are transformed by K-ras.