Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non-small cell lung cancer by downregulation of EGFR pathway.
Cannabinoid receptor-2 agonist inhibits macrophage induced EMT in non-small cell lung cancer by downregulation of EGFR pathway.
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DOI：
10.1002/mc.22451
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发表时间：
2016-12
影响因子：
4.6
通讯作者：
Ganju RK
中科院分区：
文献类型：
--
作者：
Ravi J;Elbaz M;Wani NA;Nasser MW;Ganju RK
JWH-015是大麻素受体2（CB 2）激动剂，在各种癌症类型中具有肿瘤消退特性。然而，它在肺癌中起作用的潜在机制仍然未知。肿瘤相关巨噬细胞（TAM）强度与肿瘤进展呈正相关。此外，在肿瘤部位募集的巨噬细胞通过增强上皮细胞向间充质细胞（EMT）的进展来促进肿瘤生长。在本研究中，我们分析了JWH-015通过调节EGFR信号传导对EMT和巨噬细胞浸润的作用。JWH-015抑制NSCLC细胞A549中的EMT，并且还通过下调EGFR信号传导靶点如ERK和STAT 3来逆转CALU-1细胞的间充质性质。此外，A549与M2极化巨噬细胞的体外共培养实验提供了JWH-015降低迁移和侵袭能力的证据，这通过降低FAK、VCAM 1和MMP 2的表达来证明。此外，它通过下调EGFR及其靶点减弱间充质特性来减少A549中巨噬细胞诱导的EMT。这些结果在体内皮下同基因小鼠模型中得到证实，其中JWH-015阻断肿瘤生长，并且还抑制巨噬细胞募集和肿瘤部位的EMT，其由EGFR途径调节。最后，JWH-015减少了尾静脉同系小鼠模型中的转移性病变。这些数据赋予了这种大麻素对抗增殖和抗肿瘤作用的影响，从而增强了我们对其在NSCLC中的治疗效果的理解。我们的研究结果为大麻素受体CB 2激动剂- JWH-015作为NSCLC中基于EGFR下调机制的新型潜在治疗靶点开辟了新途径。
JWH-015, a cannabinoid receptor 2 (CB2) agonist has tumor regressive property in various cancer types. However, the underlying mechanism by which it acts in lung cancer is still unknown. Tumor associated macrophage (TAM) intensity has positive correlation with tumor progression. Also, macrophages recruited at the tumor site promote tumor growth by enhancing epithelial to mesenchymal (EMT) progression. In this study, we analyzed the role of JWH-015 on EMT and macrophage infiltration by regulation of EGFR signaling. JWH-015 inhibited EMT in NSCLC cells A549 and also reversed the mesenchymal nature of CALU-1 cells by downregulation of EGFR signaling targets like ERK and STAT3. Also, in vitro co-culture experiments of A549 with M2 polarized macrophages provided evidence that JWH-015 decreased migratory and invasive abilities which was proved by reduced expression of FAK, VCAM1 and MMP2. Furthermore, it decreased macrophage induced EMT in A549 by attenuating the mesenchymal character by downregulating EGFR and its targets. These results were confirmed in an in vivo subcutaneous syngenic mouse model where JWH-015 blocks tumor growth and also inhibits macrophage recruitment and EMT at the tumor site which was regulated by EGFR pathway. Finally, JWH-015 reduced metastatic lesions in a tail vein syngenic mouse model. These data confer the impact of this cannabinoid on anti-proliferative and anti-tumorigenic effects, thus enhancing our understanding of its therapeutic efficacy in NSCLC. Our findings open new avenues for cannabinoid receptor CB2 agonist- JWH-015 as a novel and potential therapeutic target based on EGFR downregulation mechanisms in NSCLC.
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影响因子：
5.7
作者：
Qamri Z;Preet A;Nasser MW;Bass CE;Leone G;Barsky SH;Ganju RK
通讯作者：
Ganju RK
影响因子：
4.3
作者：
Ding, YB;Chen, GY;Yang, L
通讯作者：
Yang, L
影响因子：
11.2
作者：
Nasser MW;Qamri Z;Deol YS;Ravi J;Powell CA;Trikha P;Schwendener RA;Bai XF;Shilo K;Zou X;Leone G;Wolf R;Yuspa SH;Ganju RK
通讯作者：
Ganju RK
影响因子：
--
作者：
Ravi J;Sneh A;Shilo K;Nasser MW;Ganju RK
通讯作者：
Ganju RK
DOI：
10.4137/cgm.s11285
发表时间：
2014
期刊：
Cancer growth and metastasis
影响因子：
--
作者：
Goubran HA;Kotb RR;Stakiw J;Emara ME;Burnouf T
通讯作者：
Burnouf T