In search of new therapies for pancreatic cancer, cytokine pathways have attracted increasing interest in recent years. Cytokines play a vital role in the crosstalk between tumour cells and the tumour microenvironment. The related inflammatory cytokines IL-4 and IL-13 can regularly be detected at increased levels in the microenvironment of pancreatic cancer. They share a receptor heterodimer consisting of IL-4Rα and IL-13Rα1. While IL-4Rα induces a more oncogenic phenotype, the role of IL-13Rα1 was yet to be determined. ShRNA-based knockdown of IL-13Rα1 was performed in Capan-1 and MIA PaCa-2. We assessed cell growth and migratory capacities under the influence of IL-13Rα1. Pathway alterations were detected by immunoblot analysis. We now have demonstrated that the loss of IL-13Rα1 induces apoptosis in pancreatic cancer cells. This was associated with an epithelial-to-mesenchymal transition. Loss of IL-13Rα1 also abolished the effects of exogenous IL-4 and IL-13 stimulation. Interestingly, in wild type cells, cytokine stimulation caused a similar increase in migratory capacities as after IL-13Rα1 knockdown. Overall, our results indicate the vital role of IL-13Rα1 in the progression of pancreatic cancer. The differential expression of IL-4Rα and IL-13Rα1 has to be taken into account when considering a cytokine-targeted therapy in pancreatic cancer.

Novel treatment options for pancreatic cancer are desperately needed. De-regulated kinases can be regularly detected in pancreatic cancer. Multiple pathway inhibitors were developed to exploit these features, among them selective inhibitors of the c-Jun N-terminal kinase isoforms 1 and 2 (JNK1 and 2). We evaluated the effectiveness of four different JNK inhibitors on pancreatic cancer cell lines. Cell mobility and migration were evaluated in scratch assay and Boyden chamber assay. Mechanism of cell death was analyzed via apoptosis assays in FACS and immunoblotting as well as cell cycle analysis via FACS, and qPCR. JNK2 knockout cells were generated using siRNA transfection. Among the inhibitors, JNK inhibitor IX (JNK-in-IX), designed as specific inhibitor against JNK2 was proven highly effective in inhibiting cell growth, mobility and migration. We were able to show that JNK-in-IX caused DNA damage resulting in G2 arrest mediated through p53 and p21. Interestingly, JNK-in-IX acted independently of its primary target JNK2. In summary, JNK-in-IX was shown highly effective in pancreatic cancer. This study underlines the need for modeling systems in testing therapeutic options as JNK2 was previously not indicated as a potential target.