PT  - JOURNAL ARTICLE
AU  - Zerbato, Barbara
AU  - Gobbi, Maximilian
AU  - Ludwig, Tobias
AU  - Brancato, Virginia
AU  - Pessina, Alex
AU  - Brambilla, Luca
AU  - Wegner, Andre
AU  - Chiaradonna, Ferdinando
TI  - PGM3 inhibition Shows cooperative Effects With Erastin inducing Pancreatic cancer cell death via activation of the Unfolded Protein Response
AID  - 10.1101/2023.03.19.533311
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.03.19.533311
4099  - http://biorxiv.org/content/early/2023/03/23/2023.03.19.533311.short
4100  - http://biorxiv.org/content/early/2023/03/23/2023.03.19.533311.full
AB  - Pancreatic 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). Here we show the effect 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. Noteworthy, the combined treatment applied to 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. Our study discloses that HBP inhibition enhances, through UPR activation, the ERA effect and therefore might be a novel anticancer mechanism to be exploited as PDAC therapy.Competing Interest StatementThe authors have declared no competing interest.