Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling
Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling
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DOI：
10.1016/j.yexcr.2010.03.017
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发表时间：
2010-05-15
影响因子：
3.7
通讯作者：
DeMorrow, Sharon
中科院分区：
文献类型：
--
作者：
Frampton, Gabriel;Coufal, Monique;DeMorrow, Sharon
内源性大麻酰胺(AEA)和2-花生四烯基甘油(2-AG)对胆管癌细胞的生长有相反的作用。与癌症有关，Notch信号需要伽马分泌酶复合体才能激活。本研究的目的是确定内源性大麻素的相反作用是否依赖于Notch受体的不同激活，并证明这些受体的不同激活是由于含有早老素1和含有早老素2的伽马分泌酶复合体。用AEA或2-AG处理MZ-CHA-1细胞。检测Notch受体的表达、活化和核转位。在用AEA或2-AG刺激之前，通过瞬时转染Notch 1或2 shRNA载体来确定Notch 1和2在大麻素诱导效应中的具体作用。在AEA或2-AG处理后检测早老素1和2的表达，在早老素1或2低表达的细胞系中，早老素1和2参与了大麻素诱导的效应。AEA的抗增殖作用需要增加Notch 1mRNA的激活和核移位，而2-AG的促生长作用需要增加Notch 2mRNA的表达、激活和核移位。AEA增加了早老素1的表达和募集到γ-分泌酶复合体中，而2-AG增加了早老素2的表达和募集。旨在调节内源性大麻系统或模仿AEA在Notch信号通路上的作用模式的新的治疗策略的开发将被证明有利于胆管癌细胞的治疗。(C)2010 Elsevier Inc.保留所有权利。
The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the gamma-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-gamma-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the gamma-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management. (C) 2010 Elsevier Inc. All rights reserved.