Simvastatin attenuates macrophage-mediated gemcitabine resistance of pancreatic ductal adenocarcinoma by regulating the TGF-β1/Gfi-1 axis
Simvastatin attenuates macrophage-mediated gemcitabine resistance of pancreatic ductal adenocarcinoma by regulating the TGF-β1/Gfi-1 axis
复制标题
辛伐他汀通过调节 TGF-β1/Gfi-1 轴减弱巨噬细胞介导的胰腺导管腺癌吉西他滨耐药
DOI：
10.1016/j.canlet.2016.11.006
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发表时间：
2017
期刊：
影响因子：
9.7
通讯作者：
Zhongxue Su
中科院分区：
文献类型：
--
作者：
Guozhe Xian;Juan Zhao;Chengkun Qin;Zhenhai Zhang;Yanliang Lin;Zhongxue Su
胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，对几乎所有化疗药物（包括吉西他滨）都具有内在耐药性。在几种肿瘤的微环境中观察到大量的肿瘤相关巨噬细胞（TAMs），它们可以促进PDAC对吉西他滨的耐药性。在这项研究中，我们证实了在TAM条件培养基（TAM-CM）中孵育减少了吉西他滨诱导的PDAC细胞凋亡。辛伐他汀可减弱TAM介导的PDAC细胞对吉西他滨的耐药性。进一步的研究发现，辛伐他汀逆转TAM介导的Gfi-1下调和CTGF和HMGB 1上调。辛伐他汀诱导Gfi-1表达，这通过减少TAM分泌TGF-β1来增加PDAC细胞对吉西他滨的敏感性。荧光素酶报告基因检测和ChIP检测显示Gfi-1直接抑制CTGF和HMGB 1的转录。辛伐他汀还逆转了吉西他滨对TGF-β1和Gfi-1表达的影响，并降低了PDAC对吉西他滨的耐药性。这些结果提供了辛伐他汀通过阻断TGF-β1/Gfi-1轴减弱TAM介导的PDAC吉西他滨耐药性的第一个证据。这些发现表明TGF-β1/Gfi-1轴是治疗PDAC的新靶点。
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with an intrinsic resistance to almost all chemotherapeutic drugs, including gemcitabine. An abundance of tumor-associated macrophages (TAMs), which can promote the resistance of PDAC to gemcitabine, has been observed in the microenvironments of several tumors. In this study, we confirmed that incubation in TAM-conditioned medium (TAM-CM) reduces the gemcitabine-induced apoptosis of PDAC cells. Simvastatin attenuated the TAM-mediated resistance of PDAC cells to gemcitabine. Further investigation found that simvastatin reversed the TAM-mediated down-regulation of Gfi-1 and up-regulation of CTGF and HMGB1. Simvastatin induced Gfi-1 expression, which increased the sensitivity of PDAC cells to gemcitabine by decreasing TGF-β1 secretion by TAMs. A luciferase reporter assay and ChIP assay revealed that Gfi-1 directly repressed the transcription of CTGF and HMGB1. Simvastatin also reversed the effects of gemcitabine on the expression of TGF-β1 and Gfi-1 and reduced the resistance of PDAC to gemcitabine in vivo. These results provide the first evidence that simvastatin attenuates the TAM-mediated gemcitabine resistance of PDAC by blocking the TGF-β1/Gfi-1 axis. These findings suggest the TGF-β1/Gfi-1 axis as a novel therapeutic target for treating PDAC.