Nuclear activated β-catenin plays a causative role in colorectal cancers (CRC) but remains an elusive therapeutic target. Using human CRC cells harboring different Wnt/β-catenin pathway mutations in APC/KRAS or β-catenin/KRAS genes, and both genetic and pharmacological knockdown approaches, we show that oncogenic β-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 β-catenin activity. Chromatin immunoprecipitation (ChIP) assays demonstrated that β-catenin represses NHERF1 via TCF4 directly, while the association between TCF1 and the Nherf1 promoter increased upon β-catenin knockdown. To note, the occurrence of a cytostatic survival response in settings of single β-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/β-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 β-catenin knockdown alone. Collectively, our data unveil novel β-catenin/TCF-dependent mechanisms of CRC carcinogenesis, also offering preclinical proof of concept for combining β-catenin and NHERF1 pharmacological inhibitors as a mechanism-based strategy to augment apoptotic death of CRC cells refractory to current Wnt/β-catenin-targeted therapeutics
Saponaro, C., Sergio, S., Coluccia, A., De Luca, M., La Regina, G., Mologni, L., et al. (2018). β-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: Implications for a double-targeted therapy. ONCOGENE, 37(24), 3301-3316.
Citazione: | Saponaro, C., Sergio, S., Coluccia, A., De Luca, M., La Regina, G., Mologni, L., et al. (2018). β-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: Implications for a double-targeted therapy. ONCOGENE, 37(24), 3301-3316. |
Tipo: | Articolo in rivista - Articolo scientifico |
Carattere della pubblicazione: | Scientifica |
Presenza di un coautore afferente ad Istituzioni straniere: | Si |
Titolo: | β-catenin knockdown promotes NHERF1-mediated survival of colorectal cancer cells: Implications for a double-targeted therapy |
Autori: | Saponaro, C; Sergio, S; Coluccia, A; De Luca, M; La Regina, G; Mologni, L; Famiglini, V; Naccarato, V; Bonetti, D; Gautier, C; Gianni, S; Vergara, D; Salzet, M; Fournier, I; Bucci, C; Silvestri, R; Passerini, C; Maffia, M; Coluccia, A |
Autori: | |
Data di pubblicazione: | 2018 |
Lingua: | English |
Rivista: | ONCOGENE |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1038/s41388-018-0170-y |
Appare nelle tipologie: | 01 - Articolo su rivista |
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