PGM3 inhibition shows cooperative effects with erastin inducing pancreatic cancer cell death via activation of the unfolded protein response

Frontiers in Oncology

Oncology

Andre Wegner¹  Tobias Ludwig¹  Luca Brambilla²  Maximilian Gobbi²  Barbara Zerbato²  Ferdinando Chiaradonna²  Alex Pessina²  Virginia Brancato³ 

[1] Pathometabolism, Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany;Tumor Biochemistry, Biotechnology and Biosciences, University of Milano Bicocca, Milan, Italy;Tumor Biochemistry, Biotechnology and Biosciences, University of Milano Bicocca, Milan, Italy;Center for Genomic Science IIT@SEMM, Italian Institute of Technology, Milan, Italy;

关键词: hexosamine biosynthetic pathway;    unfolded protein response;    pancreatic cancer cells;    cell death;    erastin;    ferroptosis;   

DOI  :  10.3389/fonc.2023.1125855

 received in 2022-12-16, accepted in 2023-04-26,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor patient prognosis. Remarkably, PDAC is one of the most aggressive and deadly tumor types and is notorious for its resistance to all types of treatment. PDAC resistance is frequently associated with a wide metabolic rewiring and in particular of the glycolytic branch named Hexosamine Biosynthetic Pathway (HBP).MethodsTranscriptional and bioinformatics analysis were performed to obtain information about the effect of the HBP inhibition in two cell models of PDAC.Cell count, western blot, HPLC and metabolomics analyses were used to determine the impact of the combined treatment between an HBP’s Phosphoglucomutase 3 (PGM3) enzyme inhibitor, named FR054, and erastin (ERA), a recognized ferroptosis inducer, on PDAC cell growth and survival.ResultsHere we show that the combined treatment applied to different PDAC cell lines induces a significant decrease in cell proliferation and a concurrent enhancement of cell death. Furthermore, we show that this combined treatment induces Unfolded Protein Response (UPR), NFE2 Like BZIP Transcription Factor 2 (NRF2) activation, a change in cellular redox state, a greater sensitivity to oxidative stress, a major dependence on glutamine metabolism, and finally ferroptosis cell death.ConclusionOur study discloses that HBP inhibition enhances, via UPR activation, the ERA effect and therefore might be a novel anticancer mechanism to be exploited as PDAC therapy.

【 授权许可】

Unknown   
Copyright © 2023 Zerbato, Gobbi, Ludwig, Brancato, Pessina, Brambilla, Wegner and Chiaradonna