Dexamethasone Inhibits Cytokine-Induced, DUOX2-Related VEGF-A Expression and DNA damage in Human Pancreatic Cancer Cells and Growth of Pancreatic Cancer Xenografts

Wu, Y.; Konate, M. M.; Hollingshead, M.; Karim, B.; Diebold, B.; Lu, J.; Antony, S.; Meitzler, J. L.; Juhasz, A.; Jiang, G.; Dahan, I.; Roy, K.; Doroshow, J. H.

doi:10.1101/2022.02.13.480277

bioRxiv · 10.1101/2022.02.13.480277

Dexamethasone Inhibits Cytokine-Induced, DUOX2-Related VEGF-A Expression and DNA damage in Human Pancreatic Cancer Cells and Growth of Pancreatic Cancer Xenografts

Wu, Y.·Konate, M. M.·Hollingshead, M.·Karim, B.·Diebold, B.·Lu, J.·Antony, S.·Meitzler, J. L.·Juhasz, A.·Jiang, G.·Dahan, I.·Roy, K.·Doroshow, J. H.

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Abstract

Previously, we demonstrated that pro-inflammatory cytokines enhance dual oxidase 2 (DUOX2)-dependent production of reactive oxygen species by human pancreatic ductal carcinoma (PDAC) cells, and that DUOX2 expression is significantly increased in patients with early stages of PDAC. In genetically-engineered mouse models of PDAC, dexamethasone (Dex) decreases formation of pancreatic intraepithelial neoplasia (PanIn) foci as well as PDAC invasiveness. Herein, we report that Dex, in a concentration- and time-dependent fashion, inhibited pro-inflammatory cytokine (IFN-{gamma}/LPS/IL-17A/IL-4)-mediated enhancement of DUOX2 expression in BxPC-3, CFPAC-1, and AsPC-1 human PDAC cell lines, as well as DUOX2-induced DNA damage. The inhibitory effects of Dex were abolished by pre-treatment with the Dex antagonist RU-486. Examination of the human DUOX2 promoter in silico revealed a putative negative glucocorticoid receptor (GR) binding element (IRnGRE). Western analysis, using nuclear extracts from Dex-treated PDAC cells, demonstrated that Dex activated the glucocorticoid receptor in PDAC cell nuclei in the presence of certain co-repressors, such as NCoR-1/2 and histone deacetylases (HDAC1, 2, and 3). Dex produced no anti-proliferative effects on PDAC cells in vitro. However, Dex significantly decreased the growth of BxPC-3 xenografts while decreasing inflammatory and immune cell infiltration of the microenvironment, as well as the mRNA expression of DUOX2 and VEGF-A, in BxPC-3 tumors. In contrast, Dex had no effect on the growth of xenografts developed from MIA-PaCa cells that are unresponsive to pro-inflammatory cytokines in culture. In summary, these studies suggest that suppression of inflammation-related DUOX2 expression by Dex could diminish the oxidative milieu supporting PDAC growth and development.

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Wu, Y., Konate, M. M., Hollingshead, M., Karim, B., Diebold, B., Lu, J., Antony, S., Meitzler, J. L., Juhasz, A., Jiang, G., Dahan, I., Roy, K., Doroshow, J. H.. 2022-02-15. Dexamethasone Inhibits Cytokine-Induced, DUOX2-Related VEGF-A Expression and DNA damage in Human Pancreatic Cancer Cells and Growth of Pancreatic Cancer Xenografts. https://doi.org/10.1101/2022.02.13.480277

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