PGE2 released by pancreatic cancer cells undergoing ER stress transfers the stress to DCs impairing their immune function
Author(s)
Gilardini Montani, Maria Saveria
Benedetti, Rossella
Piconese, Silvia
Pulcinelli, Fabio Maria
Date Issued
2021
Type
article
Volume
20
Journal
Abstract
This study shows that pancreatic cancer cells undergoing cell death by Valproic Acid (VPA) treatment activated 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 IL-10 and IL-8 cytokines in comparison to those exposed to TSA-treated cells culture supernatant. Searching for molecular mechanisms leading to such differences, we found that VPA treatment dysregulated choline metabolism and triggered a stronger ER stress in pancreatic cancer cells than TSA, up-regulating CHOP, and activated COX2, 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 ROS, 4-HNE protein adducts and ER stress, as evidenced by the up-regulation of spliced XBP1 (XBP1s), effects that were reduced when DCs were exposed to supernatant of cancer cells treated with Celecoxib before VPA. Celecoxib indeed 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.
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