Simvastatin attenuates macrophage-mediated gemcitabine resistance of pancreatic ductal adenocarcinoma by regulating the TGF-β1/Gfi-1 axis. (28th January 2017)

• Record Type: Journal Article
• Authors: Xian, Guozhe; Zhao, Juan; Qin, Chengkun; Zhang, Zhenhai; Lin, Yanliang; Su, Zhongxue
• Is Part Of: Cancer letters. Volume 385(2017)
• Page Start: 65
• Page End: 74
• Publication Date: 2017-01-28
• Subjects: Simvastatin -- Gemcitabine -- TGF-β1 -- Gfi-1 -- Tumor-associated macrophages -- Pancreatic ductal adenocarcinoma; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.11.006
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: Simvastatin attenuated TAM-mediated gemcitabine resistance of PDAC cells. Exposure of PDAC cells to TAM-CM inhibited Gfi-1 expression. TAM-CM promoted the expression of CTGF and HMGB1 in PDAC cells. Simvastatin reversed the TAM-mediated signal response. Gfi-1 directly repressed the transcription of CTGF and HMGB1.