Acquisition of Chemoresistance and EMT Phenotype Is Linked with Activation of the Endothelin A Receptor Pathway in Ovarian Carcinoma Cells
Acquisition of Chemoresistance and EMT Phenotype Is Linked with Activation of the Endothelin A Receptor Pathway in Ovarian Carcinoma Cells
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DOI：
10.1158/1078-0432.ccr-10-2325
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发表时间：
2011-04-15
影响因子：
11.5
通讯作者：
Bagnato, Anna
中科院分区：
文献类型：
--
作者：
Rosano, Laura;Cianfrocca, Roberta;Bagnato, Anna
目的：新出现的证据表明，化疗耐药性和上皮间质转化（EMT）在癌症中的分子和表型之间的关联。内皮素-1（ET-1）/内皮素A受体（ETAR）轴通过驱动肿瘤促进效应（包括EMT）参与上皮性卵巢癌（EOC）的病理生物学。在这里，我们分析了ETAR如何调节化疗耐药性和EMT在EOC.Experimental Design：ET-1轴对细胞增殖，药物诱导的凋亡，侵袭力和EMT的影响进行了分析，在培养的EOC细胞敏感和耐顺铂和紫杉醇。在EOC异种移植物中检查响应于ETAR拮抗剂的肿瘤生长。结果：在卵巢癌耐药细胞中，ET-1和ETAR表达上调，并与丝裂原活化蛋白激酶（MAPK）和Akt磷酸化及细胞增殖有关。此外，在这些细胞中，E-cadherin转录抑制因子（包括Snail、Slug和Twist）以及间充质标志物（如波形蛋白和N-cadherin）的表达上调，并与增强的侵袭行为相关。有趣的是，用zibotentan（一种特异性ETAR拮抗剂）阻断ETAR或沉默ETAR，下调Snail活性，恢复药物对细胞毒性诱导的凋亡的敏感性，并抑制耐药细胞的侵袭性。在体内，zibotentan抑制敏感和耐药EOC异种移植瘤的肿瘤生长，并对化疗敏感。EOC人体组织的分析显示，ETAR在耐药肿瘤中过表达，并与EMT表型相关。结论：我们的数据提供了第一个证据，即阻断ETAR驱动的EMT可以克服化疗耐药性，抑制肿瘤进展，改善EOC患者的治疗结果。临床癌症研究; 17（8）; 2350-60。(C)2011年AACR。
Purpose: Emerging evidence suggests molecular and phenotypic association between chemoresistance and epithelial-mesenchymal transition (EMT) in cancer. Endothelin-1 (ET-1)/endothelin A receptor (ETAR) axis is implicated in the pathobiology of epithelial ovarian cancer (EOC) by driving tumor-promoting effects, including EMT. Here, we analyzed how ETAR regulates chemoresistance and EMT in EOC.Experimental Design: The effects of ET-1 axis on cell proliferation, drug-induced apoptosis, invasiveness, and EMT were analyzed in cultured EOC cells sensitive and resistant to cisplatinum and taxol. Tumor growth in response to ETAR antagonist was examined in EOC xenografts. ETAR expression was examined in 60 human EOC tumors by immunohistochemistry and correlated with chemoresistance and EMT.Results: In resistant EOC cells ET-1 and ETAR are upregulated, paralleled by enhanced mitogen activated protein kinase (MAPK) and Akt phosphorylation and cell proliferation. Moreover, in these cells the expression of E-cadherin transcriptional repressors, including Snail, Slug, and Twist, as well as of mesenchymal markers, such as vimentin and N-cadherin, were upregulated and linked with enhanced invasive behavior. Interestingly, ETAR blockade with zibotentan, a specific ETAR antagonist, or its silencing, downregulated Snail activity, restored drug sensitivity to cytotoxic-induced apoptosis, and inhibited the invasiveness of resistant cells. In vivo, zibotentan inhibited tumor growth of sensitive and resistant EOC xenografts, and sensitized to chemotherapy. Analysis of EOC human tissues revealed that ETAR is overexpressed in resistant tumors and is associated with EMT phenotype.Conclusions: Our data provide the first evidence that blockade of ETAR-driven EMT can overcome chemoresistance and inhibit tumor progression, improving the outcome of EOC patients' treatment. Clin Cancer Res; 17(8); 2350-60. (C) 2011 AACR.