FAAH inhibition enhances anandamide mediated anti-tumorigenic effects in non-small cell lung cancer by downregulating the EGF/EGFR pathway.
FAAH inhibition enhances anandamide mediated anti-tumorigenic effects in non-small cell lung cancer by downregulating the EGF/EGFR pathway.
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DOI：
10.18632/oncotarget.1723
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Ganju RK
中科院分区：
文献类型：
--
作者：
Ravi J;Sneh A;Shilo K;Nasser MW;Ganju RK
内源性大麻素anandamide （AEA）是一种神经递质，被证明具有抗癌作用。脂肪酸酰胺水解酶（FAAH）代谢AEA，降低其抗肿瘤活性。在本研究中，我们分析了FAAH抑制在非小细胞肺癌（NSCLC）中的作用。我们发现FAAH和被AEA激活的CB1受体在肺腺癌患者样本和NSCLC细胞系A549和H460中表达。由于合成的阿南达胺类似物（Met-F-AEA）不具有明显的抗肿瘤作用，我们将Met-F-AEA与FAAH抑制剂URB597联合使用，与单独使用Met-F-AEA相比，其体外抗肿瘤活性显著降低了表皮生长因子（EGF）诱导的增殖和趋化活性。进一步的信号机制分析表明Met-F-AEA联合URB597抑制EGFR及其下游信号通路ERK、AKT和NF-kB的活化。此外，它还能抑制MMP2分泌和应激纤维的形成。我们还发现Met-F-AEA与URB597联合可通过下调cyclin D1和CDK4的表达诱导G0/G1细胞周期阻滞，最终通过激活caspase-9和PARP导致细胞凋亡。此外，在异种移植裸鼠模型系统中，联合治疗抑制肿瘤生长。与单独使用Met-F-AEA或URB597相比，Met-F-AEA和URB597联合处理的小鼠肿瘤显示EGFR、AKT和ERK活化以及MMP2/MMP9表达降低。综上所述，这些数据表明，在EGFR过表达的NSCLC中，Met-F-AEA与FAAH抑制剂联合使用比单独使用单个化合物活性更能产生更好的治疗效果。
The endocannabinoid anandamide (AEA), a neurotransmitter was shown to have anti-cancer effects. Fatty acid amide hydrolase (FAAH) metabolizes AEA and decreases its anti-tumorigenic activity. In this study, we have analyzed the role of FAAH inhibition in non-small cell lung cancer (NSCLC). We have shown that FAAH and CB1 receptor which is activated by AEA are expressed in lung adenocarcinoma patient samples and NSCLC cell lines A549 and H460. Since the synthetic analogue of anandamide (Met-F-AEA) did not possess significant anti-tumorigenic effects, we used Met-F-AEA in combination with FAAH inhibitor URB597 which significantly reduced EGF (epidermal growth factor)-induced proliferative and chemotactic activities in vitro when compared to anti-tumorigenic activity of Met-F-AEA alone. Further analysis of signaling mechanisms revealed that Met-F-AEA in combination with URB597 inhibits activation of EGFR and its downstream signaling ERK, AKT and NF-kB. In addition, it inhibited MMP2 secretion and stress fiber formation. We have also shown that the Met-F-AEA in combination with URB597 induces G0/G1 cell cycle arrest by downregulating cyclin D1 and CDK4 expressions, ultimately leading to apoptosis via activation of caspase-9 and PARP. Furthermore, the combination treatment inhibited tumor growth in a xenograft nude mouse model system. Tumors derived from Met-F-AEA and URB597 combination treated mice showed reduced EGFR, AKT and ERK activation and MMP2/MMP9 expressions when compared to Met-F-AEA or URB597 alone. Taken together, these data suggest in EGFR overexpressing NSCLC that the combination of Met-F-AEA with FAAH inhibitor resulted in superior therapeutic response compared to individual compound activity alone.
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29.4
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