Nucleolin Targeting by N6L Inhibits Wnt/β-Catenin Pathway Activation in Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has no effective treatment. Nucleolin targeting by the pseudopeptide N6L inhibits the tumor growth and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here, we explored the pathways regulated by nucleolin and N6L in PDAC. We demonstrated that both interact with β-catenin, and that the Wnt/β-catenin pathway is activated in PDAC mouse models. Nucleolin inhibition decreases Wnt/β-catenin pathway activation in PDAC cells and tumors, and represents a new druggable pathway regulated by nucleolin. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.