Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers

WNT-CTNN1B signaling promotes cancer cell proliferation and stemness. Furthermore, recent evidence indicates that macroautophagy/autophagy regulates WNT signaling. Here we investigated the impact of inhibiting WNT signaling on autophagy in glioblastoma (GBM), a devastating brain tumor. Inhibiting TC...

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Autores: Nàger Grifo, Mireia, Crespí Sallán, Marta, Visa Pretel, Anna, Pushparaj, Charumathi, Santacana Espasa, Maria, Macià Armengol, Anna, Yeramian Hakim, Andree, Cantí Nicolás, Carles, Herreros Danés, Judit
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Recursos:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/62654
Acesso em linha:https://doi.org/10.1080/15548627.2017.1423439
http://hdl.handle.net/10459.1/62654
Access Level:acceso abierto
Palavra-chave:Glioblastoma multiforme
Autofàgia
Autophagy
Glioblastoma
CTNNB1
SQSTM1
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repository_id_str
spelling Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockersNàger Grifo, MireiaCrespí Sallán, MartaVisa Pretel, AnnaPushparaj, CharumathiSantacana Espasa, MariaMacià Armengol, AnnaYeramian Hakim, AndreeCantí Nicolás, CarlesHerreros Danés, JuditGlioblastoma multiformeAutofàgiaAutophagyGlioblastomaCTNNB1SQSTM1WNT-CTNN1B signaling promotes cancer cell proliferation and stemness. Furthermore, recent evidence indicates that macroautophagy/autophagy regulates WNT signaling. Here we investigated the impact of inhibiting WNT signaling on autophagy in glioblastoma (GBM), a devastating brain tumor. Inhibiting TCF, or silencing TCF4 or CTNNB1/β-catenin upregulated SQSTM1/p62 in GBM at transcriptional and protein levels and, in turn, autophagy. DKK1/Dickkopf1, a canonical WNT receptor antagonist, also induced autophagic flux. Importantly, TCF inhibition regulated autophagy through MTOR inhibition and dephosphorylation, and nuclear translocation of TFEB, a master regulator of lysosomal biogenesis and autophagy. TCF inhibition or silencing additionally affected GBM cell proliferation and migration. Autophagy induction followed by its blockade can promote cancer cell death. In agreement with this notion, halting both TCF-CTNNB1 and autophagy pathways decreased cell viability and induced apoptosis of GBM cells through a SQSTM1-dependent mechanism involving CASP8 (caspase 8). In vivo experiments further underline the therapeutic potential of such dual targeting in GBM.Taylor & Francis2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://doi.org/10.1080/15548627.2017.1423439http://hdl.handle.net/10459.1/62654reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)InglésReproducció del document publicat a https://doi.org/10.1080/15548627.2017.1423439Autophagy, 2018, vol. 14, núm. 4, p. 619-636(c) Taylor & Francis, 2018info:eu-repo/semantics/openAccessoai:repositori.udl.cat:10459.1/626542026-06-24T12:42:17Z
dc.title.none.fl_str_mv Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers
title Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers
spellingShingle Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers
Nàger Grifo, Mireia
Glioblastoma multiforme
Autofàgia
Autophagy
Glioblastoma
CTNNB1
SQSTM1
title_short Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers
title_full Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers
title_fullStr Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers
title_full_unstemmed Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers
title_sort Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers
dc.creator.none.fl_str_mv Nàger Grifo, Mireia
Crespí Sallán, Marta
Visa Pretel, Anna
Pushparaj, Charumathi
Santacana Espasa, Maria
Macià Armengol, Anna
Yeramian Hakim, Andree
Cantí Nicolás, Carles
Herreros Danés, Judit
author Nàger Grifo, Mireia
author_facet Nàger Grifo, Mireia
Crespí Sallán, Marta
Visa Pretel, Anna
Pushparaj, Charumathi
Santacana Espasa, Maria
Macià Armengol, Anna
Yeramian Hakim, Andree
Cantí Nicolás, Carles
Herreros Danés, Judit
author_role author
author2 Crespí Sallán, Marta
Visa Pretel, Anna
Pushparaj, Charumathi
Santacana Espasa, Maria
Macià Armengol, Anna
Yeramian Hakim, Andree
Cantí Nicolás, Carles
Herreros Danés, Judit
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Glioblastoma multiforme
Autofàgia
Autophagy
Glioblastoma
CTNNB1
SQSTM1
topic Glioblastoma multiforme
Autofàgia
Autophagy
Glioblastoma
CTNNB1
SQSTM1
description WNT-CTNN1B signaling promotes cancer cell proliferation and stemness. Furthermore, recent evidence indicates that macroautophagy/autophagy regulates WNT signaling. Here we investigated the impact of inhibiting WNT signaling on autophagy in glioblastoma (GBM), a devastating brain tumor. Inhibiting TCF, or silencing TCF4 or CTNNB1/β-catenin upregulated SQSTM1/p62 in GBM at transcriptional and protein levels and, in turn, autophagy. DKK1/Dickkopf1, a canonical WNT receptor antagonist, also induced autophagic flux. Importantly, TCF inhibition regulated autophagy through MTOR inhibition and dephosphorylation, and nuclear translocation of TFEB, a master regulator of lysosomal biogenesis and autophagy. TCF inhibition or silencing additionally affected GBM cell proliferation and migration. Autophagy induction followed by its blockade can promote cancer cell death. In agreement with this notion, halting both TCF-CTNNB1 and autophagy pathways decreased cell viability and induced apoptosis of GBM cells through a SQSTM1-dependent mechanism involving CASP8 (caspase 8). In vivo experiments further underline the therapeutic potential of such dual targeting in GBM.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1080/15548627.2017.1423439
http://hdl.handle.net/10459.1/62654
url https://doi.org/10.1080/15548627.2017.1423439
http://hdl.handle.net/10459.1/62654
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.1080/15548627.2017.1423439
Autophagy, 2018, vol. 14, núm. 4, p. 619-636
dc.rights.none.fl_str_mv (c) Taylor & Francis, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Taylor & Francis, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Taylor & Francis
publisher.none.fl_str_mv Taylor & Francis
dc.source.none.fl_str_mv reponame:Repositori Obert UdL
instname:Universitat de Lleida (UdL)
instname_str Universitat de Lleida (UdL)
reponame_str Repositori Obert UdL
collection Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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