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

Cancers

Philippe Bouvet¹  Mounira Chalabi-Dchar¹  Jerome Cros²  Anne Couvelard²  José Courty³  Matteo Ponzo³  Michele Boniotto³  Benoît Vallée³  Mélissande Cossutta³  Ilaria Cascone³  Sandrine Bourgoin-Voillard³  José L. Cohen³  Fabio Raineri³  Claire Houppe³  Damien Habert³  Anais Debesset³ 

[1] Centre de Recherche en Cancérologie de Lyon, Cancer Cell Plasticity Department, University of Lyon, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, 69008 Lyon, France;Département de Pathologie, Hôpital Bichat APHP DHU UNITY, 75018 Paris, France;University Paris Est Créteil, INSERM, IMRB, 94010 Créteil, France;

关键词: pancreatic ductal adenocarcinoma;    nucleolin;    N6L;    Wnt/β-catenin pathway;    tumor microenvironment;    cancer therapy;   

DOI  :  10.3390/cancers13122986

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown