The absence of Peroxiredoxin-1 in human pancreatic ductal adenocarcinoma (PDAC) markedly reduces cell survival and tumor growth when coupled with the inhibition of Ref-1 redox signaling
Menée à l'aide de lignées cellulaires et de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence une réduction de la survie globale et de la croissance tumorale lorsque la peroxyrédoxine n'est pas exprimée par les cellules cancéreuses et que le facteur Ref-1 est inhibé
Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to therapy, surviving despite hypoxia, oxidative stress, and nutrient deprivation. Redox effector factor-1 (Ref-1) regulates several oncogenic transcription factors (TFs) and is controlled by peroxiredoxins (PRDX). We investigated how Ref-1 inhibition by APX2014, combined with PRDX expression, affects pancreatic cancer cells from multiple patient lines. Silencing or CRISPR/Cas9 knockout of PRDX1—but not PRDX2-6—sensitized PDAC cell lines to APX2014 both in vitro and in vivo without affecting Ref-1's DNA repair function of apurinic/apyrimidinic endonuclease. The combination of PRDX1 loss and APX2014 treatment increased apoptosis and decreased TF activity (NF-
κB, HIF-1α) and their downstream targets, TNFAIP2, Survivin, and CA9. A 3D co-culture with PRDX1-null tumor spheroids and cancer-associated fibroblasts (CAFs) showed that (i) Ref-1 inhibition impaired PRDX1-null tumor growth, and (ii) PRDX1 loss reduced CAF viability, highlighting redox crosstalk within the tumor microenvironment (TME). In a PDAC xenograft model, PRDX1-knockout tumors treated with APX2014 had smaller volumes, lighter weights, lower Ref-1, and decreased Ki-67, with improved animal survival. Patient microarrays indicated increased Ref-1 and PRDX1 levels versus normal tissue, emphasizing their clinical relevance. Overall, these data identify PRDX1 as a key factor for PDAC's susceptibility to Ref-1 blockade, suggesting dual targeting could disrupt TME redox signaling, limit tumor progression, and improve APX therapy. These findings support dual targeting of Ref-1 and PRDX1 as a promising therapeutic approach in PDAC and other redox-driven cancers.
Redox Biology , article en libre accès, 2025