Journal
CANCER LETTERS
Volume 508, Issue -, Pages 1-12Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.03.003
Keywords
Co-inhibition; Combination therapy; NF-kappa B; Pancreatic cancer; Synergy
Categories
Funding
- National Natural Science Foundation of China [81573009]
- China Postdoctoral Science Foundation [2019M650571]
- Beijing Natural Science Foundation [Z190022]
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2019I2M1001]
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The study confirmed the pro-tumor effects of IL-17 and Notch pathways in PanIN/PDAC progression and identified a positive correlation between IL-17 and Notch. Furthermore, co-inhibition of IL-17 and Notch pathways was shown to enhance therapeutic efficacy by restricting tumor growth.
Interleukin (IL)-17 is a prominent cytokine that promotes pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC) and is associated with the oncogenic pathways in tumor progression. However, the mechanism and therapeutic value of the IL-17 axis remain unclear. In this study, we verified the activation of the IL-17 and Notch pathways in PanIN/PDAC via complementary approaches and validated their pro-tumor effects on tumor progression. Additionally, we found a positive correlation between IL-17 and Notch; the IL-17 axis can upregulate Notch activity via the canonical NF-kappa B pathway in vitro, thus synergistically promoting PanIN/PDAC. Furthermore, we observed that the co-inhibition of IL-17 and the Notch pathway can enhance the therapeutic effect by restricting tumor growth in vivo. Our study highlights the synergistic effect of the IL-17 axis and Notch pathway in promoting PanIN/PDAC and further suggests that IL-17-Notch co-inhibition is a novel therapeutic strategy with superior potential in treating PDAC.
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