Simvastatin attenuates macrophage-mediated gemcitabine resistance of pancreatic ductal adenocarcinoma by regulating the TGF-β1/Gfi-1 axis.

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.

Xian G ，Zhao J ，Qin C ，Zhang Z ，Lin Y ，Su Z ... -  《-》

OSI-027 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine both in vitro and in vivo.

Zhi X ，Chen W ，Xue F ，Liang C ，Chen BW ，Zhou Y ，Wen L ，Hu L ，Shen J ，Bai X ，Liang T ... -  《Oncotarget》

TRIM11 suppresses ferritinophagy and gemcitabine sensitivity through UBE2N/TAX1BP1 signaling in pancreatic ductal adenocarcinoma.

Gemcitabine is first-line chemotherapy for pancreatic cancer, however, the development of resistance limits its effectiveness. The tripartite motif-containing 11 (TRIM11) protein plays crucial roles in tumor development and undergoes auto-polyubiquitination to promote interactions in selective autophagy. Therefore, Understanding whether TRIM11 is involved in ferritinophagy and gemcitabine resistance in pancreatic cancer is critical in developing pancreatic cancer therapeutics. TRIM11 expression was validated by Western blot analysis, real-time polymease chain reaction, and immunohistochemical staining. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Colony formation assays were performed to investigate pancreatic ductal adenocarcinomas (PDAC) cell viability. Mouse xenograft model of PDAC cells was established to verify the role of TRIM11 in vivo. Coimmunoprecipitation was used to identify the reciprocal regulation between TRIM11 and UBE2N. In this study, we found that TRIM11 expression were higher in PDAC cells and tissues. TRIM11 overexpression promotes PDAC cell proliferation in vitro and tumor growth in vivo. Decreased expression of TRIM11 in PDAC patients is associated with decreased UBE2N and increased TAX1BP1 expression. Coimmunoprecipitation established that TRIM11 interacts and colocalizes with UBE2N. Mechanistically, TRIM11 promoted gemcitabine resistance and suppressed ferritinophagy through UBE2N-TAX1BP1 signaling. Our findings identify TRIM11 as a key regulator of TAX1BP1 signaling with a crucial role in ferritinophagy and gemcitabine resistance in PDAC.

Shang M ，Weng L ，Xu G ，Wu S ，Liu B ，Yin X ，Mao A ，Zou X ，Wang Z ... -  《-》

Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment.

Liu Q ，Wu H ，Li Y ，Zhang R ，Kleeff J ，Zhang X ，Cui M ，Liu J ，Li T ，Gao J ，Pan B ，Wu W ，Wang W ，Zhou L ，Guo J ，Dai M ，Zhang T ，Liao Q ，Lu Z ，Zhao Y ... -  《-》

Melittin inhibits tumor growth and decreases resistance to gemcitabine by downregulating cholesterol pathway gene CLU in pancreatic ductal adenocarcinoma.

Melittin is a Chinese traditional medicine for treating chronic inflammation, immunological diseases and cancers, however, the efficacy of melittin and its mechanism for treating pancreatic ductal adenocarcinoma (PDAC) are still unknown. Here we investigated the anti-cancer activity of melittin and its regulated mechanism(s) in the PDAC models. Melittin was found to suppress tumor growth by promoting cell apoptosis and cell-cycle arrest. Interestingly, the microarray analyses demonstrated that melittin significantly regulated cholesterol biosynthesis pathway during treatment. For instance, the cholesterol pathway gene clusterin (CLU) was highly downregulated by melittin which also enhanced gemcitabine sensitivity in PDAC cells by inhibiting CLU expression. In contrast, overexpression of CLU significantly diminished melittin mediated tumor suppression and gemcitabine sensitization, suggesting that CLU is the target of melittin. Furthermore, in the xenograft mouse model, the combination therapy of melittin and gemcitabine is more efficacious for inhibiting PDAC tumor growth than either single regimen. Taken together, our study has indicated that melittin is capable of suppressing tumor growth and promoting gemcitabine sensitivity in PDAC by downregulating cholesterol pathway.

Wang X ，Xie J ，Lu X ，Li H ，Wen C ，Huo Z ，Xie J ，Shi M ，Tang X ，Chen H ，Peng C ，Fang Y ，Deng X ，Shen B ... -  《-》