biostudies-literatureNagaraju GPThe University of Alabama at BirminghamComprehensive Cancer Center, University of Chicago Medical CenterNCI NIH HHSMorningside FoundationUniversity of Alabama101881https://www.ebi.ac.uk/biostudies/studies/S-EPMC11866435biostudies-literatureUnknown6(1)Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-aCell reports. MedicineMechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine.PMC11866435P30 CA0827095P30CAO13148-47Golivi YFoote JBManne UMasood AReddy SPAkce MBandi DSRYoon KJAlese OBHerting CEl-Rayes BFSarvesh SCarstens JLBhasin MKSwitchenko JNagaraju GPKhaliq AMSukhatme VPSaddala MSLesinski GBfalseMechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine.Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-a2025-01-01T00:00:00Z2025 Jan2026-05-26T14:01:21.004Z2025-04-04T13:10:59.497ZS-EPMC118664353973000110.1016/j.xcrm.2024.101881