Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with few therapeutic options. The identification of new promising targets is, therefore, an urgent need. Using available transcriptomic datasets, we first found that Peroxiredoxin-1 gene (PRDX1) expression was significantly increased in human pancreatic tumors, but not in the other gastrointestinal cancers; its high expression correlated with shortened patient survival. We confirmed by immunostaining on mouse pancreata the increased Peroxiredoxin-I protein (PRX-I) expression in pancreatic neoplastic lesions and PDAC. To question the role of PRX-I in pancreatic cancer, we genetically inactivated its expression in multiple human PDAC cell lines, using siRNA and CRISPR/Cas9. In both strategies, PRX-I ablation led to reduced survival of PDAC cells. This was mainly due to an increase in the production of reactive oxygen species (ROS), accumulation of oxidative DNA damage (i.e., 8-oxoguanine), and cell cycle blockade at G2/M. Finally, we found that PRX-I ablation disrupts the autophagic flux in PDAC cells, which is essential for their survival. This proof-of-concept study supports a pro-oncogenic role for PRX-I in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers in the world, with few, if any, efficient treatments
Since we demonstrated that PRX-I promotes signal transducer and activator of transcription 3 (STAT3) activation, we wondered if STAT3 is responsible for disrupted autophagy observed in cells lacking PRX-I
Besides STAT3, AMP-activated protein kinase (AMPK) has been described as an activator of autophagy [32,33]; we have found that the phosphorylation of Acetyl-CoA carboxylase (ACC), a direct substrate of AMPK [34], was significantly decreased in PRDX1KO compared with PRDX1WT cells, highlighting a reduction in AMPK downstream activity
Summary
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers in the world, with few, if any, efficient treatments. At the molecular level, emerging research revealed the presence of redox-sensitive mechanisms essential for the maintenance of PDAC growth [9,10] These include the modulation of reactive oxygen species (ROS) levels, and the control of the expression and activity of the redox master regulator, nuclear factor erythroid 2-related factor 2 (NRF2), as well as other important antioxidant enzymes [9,10]. On this basis, Peroxiredoxins (PRXs) constitute an important checkpoint for tumor development and growth [11], as they regulate the intracellular levels of various ROS (i.e., hydrogen peroxide) and influence the activation of pro-oncogenic signaling cascades, such as Extracellular signal-regulated kinases/mitogen-. Our present results support a pro-oncogenic role for PRX-I in PDAC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
