Blocking endothelin-1-receptor/β-catenin circuit sensitizes to chemotherapy in colorectal cancer.
Blocking endothelin-1-receptor/β-catenin circuit sensitizes to chemotherapy in colorectal cancer.
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DOI：
10.1038/cdd.2017.121
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发表时间：
2017-10
影响因子：
12.4
通讯作者：
Bagnato A
中科院分区：
文献类型：
--
作者：
Cianfrocca R;Rosanò L;Tocci P;Sestito R;Caprara V;Di Castro V;De Maria R;Bagnato A
在结直肠癌（CRC）中观察到的对常规化疗药物的有限临床反应可能与过度活化的β-连环蛋白信号传导和CRC干细胞样细胞（CRC-SC）中的其他通路之间的联系有关。在这里，我们显示了内皮素-1（ET-1）/ET-1受体（ET-1 R）信号传导和β-连环蛋白通路之间的机制联系，通过与信号传导因子β-arrestin 1（β-arr 1）的特异性相互作用，启动信号级联反应作为信号复合物的一部分。使用一组患者来源的CRC-SC，我们表明这些细胞分泌ET-1并表达ETAR和β-arr 1，并且ETAR/β-arr 1轴的激活促进与β-连环蛋白信号传导的串扰，以维持干性、上皮向间质转化（EMT）表型和对化疗的反应。在ETAR激活后，β-arr 1作为转录共激活因子与β-catenin结合，从而促进与β-catenin/TFC 4和p300的核复合物以及组蛋白乙酰化，诱导靶基因（如ET-1）上的染色质重组。ET-1的转录增强增加了自我维持的ET-1/β-catenin网络。所有这些发现为靶向ET-1 R以阻碍下游β-catenin/ET-1自分泌回路提供了强有力的理论基础。有趣的是，马昔腾坦（一种ETAR和ETBR双重拮抗剂，能够干扰肿瘤和微环境）治疗可破坏ET-1 R/β-arr 1-β-catenin相互作用，损害参与细胞存活、EMT、侵袭的途径，并增强对奥沙利铂（OX）和5-氟尿嘧啶（5-FU）的敏感性。在CRC-SC异种移植物中，马昔腾坦与OX或5-FU联合可增强细胞毒性药物的治疗作用。总之，这些结果提供了ET-1 R如何协同β-catenin信号传导的机制见解，并提供了一种基于马昔腾坦和化疗联合治疗CRC的新型治疗策略，可能使肿瘤显示ETAR和β-catenin高表达的患者受益。
The limited clinical response to conventional chemotherapeutics observed in colorectal cancer (CRC) may be related to the connections between the hyperactivated β-catenin signaling and other pathways in CRC stem-like cells (CRC-SC). Here, we show the mechanistic link between the endothelin-1 (ET-1)/ET-1 receptor (ET-1R) signaling and β-catenin pathway through the specific interaction with the signal transducer β-arrestin1 (β-arr1), which initiates signaling cascades as part of the signaling complex. Using a panel of patient-derived CRC-SC, we show that these cells secrete ET-1 and express ETAR and β-arr1, and that the activation of ETAR/β-arr1 axis promotes the cross-talk with β-catenin signaling to sustain stemness, epithelial-to-mesenchymal transition (EMT) phenotype and response to chemotherapy. Upon ETAR activation, β-arr1 acts as a transcription co-activator that binds β-catenin, thereby promoting nuclear complex with β-catenin/TFC4 and p300 and histone acetylation, inducing chromatin reorganization on target genes, such as ET-1. The enhanced transcription of ET-1 increases the self-sustained ET-1/β-catenin network. All these findings provide a strong rationale for targeting ET-1R to hamper downstream β-catenin/ET-1 autocrine circuit. Interestingly, treatment with macitentan, a dual ETAR and ETBR antagonist, able to interfere with tumor and microenvironment, disrupts the ET-1R/β-arr1-β-catenin interaction impairing pathways involved in cell survival, EMT, invasion, and enhancing sensitivity to oxaliplatin (OX) and 5-fluorouracil (5-FU). In CRC-SC xenografts, the combination of macitentan and OX or 5-FU enhances the therapeutic effects of cytotoxic drugs. Together, these results provide mechanistic insight into how ET-1R coopts β-catenin signaling and offer a novel therapeutic strategy to manage CRC based on the combination of macitentan and chemotherapy that might benefit patients whose tumors show high ETAR and β-catenin expression.
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DOI：
10.1158/1078-0432.ccr-14-3195
发表时间：
2015-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kim SJ;Lee HJ;Kim MS;Choi HJ;He J;Wu Q;Aldape K;Weinberg JS;Yung WK;Conrad CA;Langley RR;Lehembre F;Regenass U;Fidler IJ
通讯作者：
Fidler IJ
影响因子：
3.8
作者：
Li J;Zhou BP
通讯作者：
Zhou BP
上皮-间质转化与球体来源的干样结肠癌细胞干性的维持相关。
影响因子：
3.7
作者：
Han XY;Wei B;Fang JF;Zhang S;Zhang FC;Zhang HB;Lan TY;Lu HQ;Wei HB
通讯作者：
Wei HB
影响因子：
15.9
作者：
Lee, Ho Jeong;Hanibuchi, Masaki;Fidler, Isaiah J.
通讯作者：
Fidler, Isaiah J.
影响因子：
2.5
作者：
Liakou, Paraskevi;Tepetes, Kostantinos;Rassidakis, George Z.
通讯作者：
Rassidakis, George Z.