Cancer lettersNov 15, 2016

Simvastatin reduces immune cell-driven resistance to gemcitabine in pancreatic cancer by controlling the TGF-β1/Gfi-1 pathway

Updated Mar 3, 2026

Abstract

Simvastatin may reduce the resistance of pancreatic ductal adenocarcinoma (PDAC) cells to gemcitabine.

Incubation in tumor-associated macrophage-conditioned medium decreases gemcitabine-induced cell death in PDAC.
Simvastatin appears to counteract the resistance of PDAC cells to gemcitabine promoted by tumor-associated macrophages.
Gfi-1 expression is increased by simvastatin, leading to enhanced sensitivity of PDAC cells to gemcitabine.
Simvastatin lowers TGF-β1 secretion from tumor-associated macrophages, which may contribute to its effects.
Gfi-1 is shown to directly inhibit the expression of CTGF and HMGB1, which are associated with PDAC resistance.

Simplified

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.

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