PGE2 Released by Pancreatic Cancer Cells Undergoing ER Stress Transfers the Stress to DCs Impairing Their Immune Function
Maria Saveria Gilardini Montani, Rossella Benedetti, Silvia Piconese, Fabio M. Pulcinelli, Anna Maria Timperio, Maria Anele Romeo, Laura Masuelli, Maurizio Mattei, Roberto Bei, Gabriella D’Orazi, Mara Cirone
Abstract
Abstract This study shows that pancreatic cancer cells undergoing cell death by valproic acid (VPA) treatment activated dendritic cells (DCs) more efficiently than those treated with trichostatin A (TSA), as demonstrated by CD86 and CD80 surface expression. Surprisingly though, DCs cultured in the presence of supernatant derived from VPA-treated cancer cells showed a reduced allostimulatory capacity and an increased release of IL10 and IL8 cytokines in comparison with those exposed to TSA-treated cell culture supernatant. Searching for molecular mechanisms leading to such differences, we found that VPA treatment dysregulated choline metabolism and triggered a stronger endoplasmic reticulum (ER) stress in pancreatic cancer cells than TSA, upregulating CCAAT/enhancer-binding protein homologous protein, and activated cyclooxygenase-2, thus promoting the release of prostaglandin (PG) E2. Interestingly, dysfunctional DCs cultured in the presence of VPA-treated cells culture supernatant showed a higher level of intracellular reactive oxygen species, 4-hydroxy-trans-2-nonenal protein adducts, and ER stress, as evidenced by the upregulation of spliced X-box binding protein 1 (XBP1s), effects that were reduced when DCs were exposed to supernatant of cancer cells treated with Celecoxib before VPA. Celecoxib prevented PGE2 release, restoring the function of DCs exposed to VPA-treated cells culture supernatant, and a similar effect was obtained by silencing XBP1s in DCs treated with VPA-treated cells culture supernatant. These results suggest that PGE2 could be one of the yet unidentified factors able to transfer the stress from cancer cells to DCs, resulting in an impairment of their function.