Titre :

β-catenin knockdown promotes nherf1-mediated survival of colorectal cancer cells: implications for a double-targeted therapy

Auteur(s) :

Saponaro, Concetta [Auteur]
Sergio, Sara [Auteur]
Coluccia, Antonio [Auteur]
De Luca, Maria [Auteur]
La Regina, Giuseppe [Auteur]
Mologni, Luca [Auteur]
Famiglini, Valeria [Auteur]
Naccarato, Valentina [Auteur]
Bonetti, Daniela [Auteur]
Gautier, Candice [Auteur]
Gianni, Stefano [Auteur]
Vergara, Daniele [Auteur]
Salzet, Michel [Auteur]
Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192
FOURNIER, Isabelle [Auteur]
Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192
Bucci, Cecilia [Auteur]
Silvestri, Romano [Auteur]
Passerini, Carlo Gambacorti [Auteur]
Maffia, Michele [Auteur]
Coluccia, Addolorata Maria Luce [Auteur]

Titre de la revue :

Oncogene

Nom court de la revue :

Oncogene

Date de publication :

2018-03-19

ISSN :

1476-5594

Discipline(s) HAL :

Sciences du Vivant [q-bio]

Résumé en anglais : [en]

Nuclear activated beta-catenin plays a causative role in colorectal cancers (CRC) but remains an elusive therapeutic target. Using human CRC cells harboring different Wnt/beta-catenin pathway mutations in APC/KRAS or ...
Lire la suite >Nuclear activated beta-catenin plays a causative role in colorectal cancers (CRC) but remains an elusive therapeutic target. Using human CRC cells harboring different Wnt/beta-catenin pathway mutations in APC/KRAS or beta-catenin/KRAS genes, and both genetic and pharmacological knockdown approaches, we show that oncogenic beta-catenin signaling negatively regulates the expression of NHERF1 (Na(+)/H(+) exchanger 3 regulating factor 1), a PDZ-adaptor protein that is usually lost or downregulated in early dysplastic adenomas to exacerbate nuclear beta-catenin activity. Chromatin immunoprecipitation (ChIP) assays demonstrated that beta-catenin represses NHERF1 via TCF4 directly, while the association between TCF1 and the Nherf1 promoter increased upon beta-catenin knockdown. To note, the occurrence of a cytostatic survival response in settings of single beta-catenin-depleted CRC cells was abrogated by combining NHERF1 inhibition via small hairpin RNA (shRNA) or RS5517, a novel PDZ1-domain ligand of NHERF1 that prevented its ectopic nuclear entry. Mechanistically, dual NHERF1/beta-catenin targeting promoted an autophagy-to-apoptosis switch consistent with the activation of Caspase-3, the cleavage of PARP and reduced levels of phospho-ERK1/2, Beclin-1, and Rab7 autophagic proteins compared with beta-catenin knockdown alone. Collectively, our data unveil novel beta-catenin/TCF-dependent mechanisms of CRC carcinogenesis, also offering preclinical proof of concept for combining beta-catenin and NHERF1 pharmacological inhibitors as a mechanism-based strategy to augment apoptotic death of CRC cells refractory to current Wnt/beta-catenin-targeted therapeutics.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Établissement(s) :

INSERM
Université de Lille

Collections :

• Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192

Date de dépôt :

2022-06-15T13:57:35Z