FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin via SHP dependent inhibition of Bcl-xL expression.
FXR agonists enhance the sensitivity of biliary tract cancer cells to cisplatin via SHP dependent inhibition of Bcl-xL expression.
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FXR 激动剂通过 SHP 依赖性抑制 Bcl-xL 表达增强胆道癌细胞对顺铂的敏感性
DOI：
10.18632/oncotarget.8964
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发表时间：
2016-06-07
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Wang W;Zhan M;Li Q;Chen W;Chu H;Huang Q;Hou Z;Man M;Wang J
化疗耐药在包括胆囊癌 (GBC) 和胆管癌 (CC) 在内的胆道癌 (BTC) 患者中很常见。因此，有必要寻找有效的BTC化疗药物。在本研究中，我们首次测试了法尼醇X受体（FXR）激动剂GW4064和CDCA（鹅去氧胆酸）联合顺铂（CDDP）对增加BTC化疗敏感性的作用。我们的结果表明，CDDP 与 FXR 激动剂共同处理可显着增强 BTC 细胞的化疗敏感性。从机制上讲，我们发现 FXR 的激活诱导小异二聚体伴侣 (SHP) 的表达，进而抑制信号转导子和转录激活子 3 (STAT3) 磷酸化，并导致 BTC 细胞中 Bcl-xL 表达下调，从而导致对 CDDP 的敏感性增加。此外，对荷瘤小鼠的实验表明，GW4064/CDDP联合治疗通过上调SHP表达和下调STAT3磷酸化来抑制体内肿瘤生长。这些结果表明 CDDP 与 FXR 激动剂联合可能成为 BTC 的潜在新治疗策略。
Chemoresistance is common in patients with biliary tract cancer (BTC) including gallbladder cancer (GBC) and cholangiocarcinoma (CC). Therefore, it is necessary to identify effective chemotherapeutic agents for BTC. In the present study, we for the first time tested the effect of farnesoid X receptor (FXR) agonists GW4064 and CDCA (chenodeoxycholic acid) in combination with cisplatin (CDDP) on increasing the chemosensitivity in BTC. Our results show that co-treatment of CDDP with FXR agonists remarkably enhance chemosensitivity of BTC cells. Mechanistically, we found that activation of FXR induced expression of small heterodimer partner (SHP), which in turn inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and resulted in down-regulation of Bcl-xL expression in BTC cells, leading to increased susceptibility to CDDP. Moreover, the experiments on tumor-bearing mice showed that GW4064/CDDP co-treatment inhibited the tumor growth in vivo by up-regulating SHP expression and down-regulating STAT3 phosphorylation. These results suggest CDDP in combination with FXR agonists could be a potential new therapeutic strategy for BTC.
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影响因子：
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