biostudies-literatureMijit MNEI NIH HHSNHLBI NIH HHSNCI NIH HHSNational Institutes of Health1146115https://www.ebi.ac.uk/biostudies/studies/S-EPMC10174294biostudies-literatureUnknown10Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) is characterized by a profound inflammatory tumor microenvironment (TME) with high heterogeneity, metastatic propensity, and extreme hypoxia. The integrated stress response (ISR) pathway features a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) and regulate translation in response to diverse stress conditions, including hypoxia. We previously demonstrated that eIF2 signaling pathways were profoundly affected in response to Redox factor-1 (Ref-1) knockdown in human PDAC cells. Ref-1 is a dual function enzyme with activities of DNA repair and redox signaling, responds to cellular stress, and regulates survival pathways. The redox function of Ref-1 directly regulates multiple transcription factorsFrontiers in medicineActivation of the integrated stress response (ISR) pathways in response to Ref-1 inhibition in human pancreatic cancer and its tumor microenvironment.PMC10174294R01 CA282478P30 CA082709R01 CA167291R01 HL140961R01 CA205166R01 EY031939R01 CA231267U01 CA274304U01 HL143403Gampala SKelley MRStaschke KAMijit MKlunk AJFishel MLBoner MKpenu ECordova RAZhang CfalseActivation of the integrated stress response (ISR) pathways in response to Ref-1 inhibition in human pancreatic cancer and its tumor microenvironment.Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) is characterized by a profound inflammatory tumor microenvironment (TME) with high heterogeneity, metastatic propensity, and extreme hypoxia. The integrated stress response (ISR) pathway features a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) and regulate translation in response to diverse stress conditions, including hypoxia. We previously demonstrated that eIF2 signaling pathways were profoundly affected in response to Redox factor-1 (Ref-1) knockdown in human PDAC cells. Ref-1 is a dual function enzyme with activities of DNA repair and redox signaling, responds to cellular stress, and regulates survival pathways. The redox function of Ref-1 directly regulates multiple transcription factors2023-01-01T00:00:00Z20232026-05-28T23:00:17.027Z2026-04-08T03:24:41.116ZS-EPMC101742943718135710.3389/fmed.2023.1146115