Ascochlorin Enhances the Sensitivity of Doxorubicin Leading to the Reversal of Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma
Ascochlorin Enhances the Sensitivity of Doxorubicin Leading to the Reversal of Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma
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DOI：
10.1158/1535-7163.mct-16-0391
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发表时间：
2016-12-01
影响因子：
5.7
通讯作者：
Sethi, Gautam
中科院分区：
文献类型：
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作者：
Dai, Xiaoyun;Ahn, Kwang Seok;Sethi, Gautam
越来越多的证据表明，晚期肝癌的上皮细胞向间质细胞转化（EMT）不仅具有自我更新和癌症进展的能力，而且对常规化疗和放疗具有更大的抵抗力。在这里，我们报告，子囊二氢卟酚（ASC），类异戊二烯抗生素，可以加强多柔比星对HCCLM 3，SNU 387，SNU 49，和SK-Hep-1肝癌细胞的细胞毒性作用，其中有一个主要的间充质签名与低表达的E-钙粘蛋白，但高表达的N-钙粘蛋白。ASC的共同管理减少阿霉素诱导的侵袭/迁移和调制间充质细胞的EMT特性。这个过程可能是由E-钙粘蛋白抑制子Snail和Slug介导的。此外，ASC通过直接抑制STAT 3与Snail启动子的结合来增加对多柔比星治疗的敏感性。我们还观察到ASC显著增强了多柔比星对HCCLM3_Luc原位小鼠模型中肿瘤生长和转移的抑制作用。总的来说，我们的数据表明，ASC可以增加对阿霉素治疗的敏感性，并通过下调STAT 3-Snail表达来逆转EMT表型，这可能构成针对肝细胞癌的新治疗方法的基础。(C)2016年AACR。
Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo-and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. (C) 2016 AACR.