T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma

T-type Ca2+ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) s...

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Autores: Visa Pretel, Anna, Crespí Sallán, Marta, Maiques Carlos, Oscar, Alza, Lía, Talavera, Elisabeth, López Ortega, Ricard, Santacana Espasa, Maria, Herreros Danés, Judit, Cantí Nicolás, Carles
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/65789
Acceso en línea:https://doi.org/10.1158/0008-5472.CAN-18-1924
http://hdl.handle.net/10459.1/65789
Access Level:acceso abierto
Palabra clave:Voltage-gated calcium channels
Autophagy
Temozolomide
Glioblastoma
Glioblastoma multiforme
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spelling T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastomaVisa Pretel, AnnaCrespí Sallán, MartaMaiques Carlos, OscarAlza, LíaTalavera, ElisabethLópez Ortega, RicardSantacana Espasa, MariaHerreros Danés, JuditCantí Nicolás, CarlesVoltage-gated calcium channelsAutophagyTemozolomideGlioblastomaGlioblastoma multiformeT-type Ca2+ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacological blockers have limited selectivity for TTCC, and are unable to distinguish between TTCC isoforms. Here we analyzed the expression of TTCC transcripts in human GBM cells and show a prevalence of Cav3.1 mRNAs. Infection of GBM cells with lentiviral particles carrying shRNA against Cav3.1 resulted in GBM cell death by apoptosis. We generated a murine GBM xenograft via subcutaneous injection of U87-MG GBM cells and found that tumor size was reduced when Cav3.1 expression was silenced. Furthermore, we developed an in vitro model of temozolomide-resistant GBM that showed increased expression of Cav3.1 accompanied by activation of macroautophagy. We confirmed a positive correlation between Cav3.1 and autophagic markers in both GBM cultures and biopsies. Of note, Cav3.1 knockdown resulted in transcriptional downregulation of p62/SQSTM1 and deficient autophagy. Together, these data identify Cav3.1 channels as potential targets for slowing GBM progression and recurrence based on their role in regulating autophagy.Paired biopsies of primary and recurrent GBMs were obtained through Biobank Networkfrom Carlos III Health Institute (NavarraBiomed, Toledo and Basque Biobanks). This work was funded by Instituto de Salud Carlos III/FEDER (“Una manera de hacer Europa”; PI13/01980 to JH). Work supported by IRBLleida Biobank (B.0000682) and PLATAFORMA BIOBANCOS PT17/0015/0027/. MCS and AV held predoctoral fellowships from University of Lleida (UdL).American Association for Cancer Research2019202020192019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://doi.org/10.1158/0008-5472.CAN-18-1924http://hdl.handle.net/10459.1/65789http://hdl.handle.net/10459.1/65789reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1158/0008-5472.CAN-18-1924Cancer Research, 2019, vol. 79, núm. 8, p. 1857-1868(c) American Association for Cancer Research, 2019info:eu-repo/semantics/openAccessoai:recercat.cat:10459.1/657892026-05-29T05:05:01Z
dc.title.none.fl_str_mv T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma
title T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma
spellingShingle T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma
Visa Pretel, Anna
Voltage-gated calcium channels
Autophagy
Temozolomide
Glioblastoma
Glioblastoma multiforme
title_short T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma
title_full T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma
title_fullStr T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma
title_full_unstemmed T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma
title_sort T-type Cav3.1 channels mediate progression and chemotherapeutic resistance in glioblastoma
dc.creator.none.fl_str_mv Visa Pretel, Anna
Crespí Sallán, Marta
Maiques Carlos, Oscar
Alza, Lía
Talavera, Elisabeth
López Ortega, Ricard
Santacana Espasa, Maria
Herreros Danés, Judit
Cantí Nicolás, Carles
author Visa Pretel, Anna
author_facet Visa Pretel, Anna
Crespí Sallán, Marta
Maiques Carlos, Oscar
Alza, Lía
Talavera, Elisabeth
López Ortega, Ricard
Santacana Espasa, Maria
Herreros Danés, Judit
Cantí Nicolás, Carles
author_role author
author2 Crespí Sallán, Marta
Maiques Carlos, Oscar
Alza, Lía
Talavera, Elisabeth
López Ortega, Ricard
Santacana Espasa, Maria
Herreros Danés, Judit
Cantí Nicolás, Carles
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Voltage-gated calcium channels
Autophagy
Temozolomide
Glioblastoma
Glioblastoma multiforme
topic Voltage-gated calcium channels
Autophagy
Temozolomide
Glioblastoma
Glioblastoma multiforme
description T-type Ca2+ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacological blockers have limited selectivity for TTCC, and are unable to distinguish between TTCC isoforms. Here we analyzed the expression of TTCC transcripts in human GBM cells and show a prevalence of Cav3.1 mRNAs. Infection of GBM cells with lentiviral particles carrying shRNA against Cav3.1 resulted in GBM cell death by apoptosis. We generated a murine GBM xenograft via subcutaneous injection of U87-MG GBM cells and found that tumor size was reduced when Cav3.1 expression was silenced. Furthermore, we developed an in vitro model of temozolomide-resistant GBM that showed increased expression of Cav3.1 accompanied by activation of macroautophagy. We confirmed a positive correlation between Cav3.1 and autophagic markers in both GBM cultures and biopsies. Of note, Cav3.1 knockdown resulted in transcriptional downregulation of p62/SQSTM1 and deficient autophagy. Together, these data identify Cav3.1 channels as potential targets for slowing GBM progression and recurrence based on their role in regulating autophagy.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019
2020
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/10.1158/0008-5472.CAN-18-1924
http://hdl.handle.net/10459.1/65789
http://hdl.handle.net/10459.1/65789
url https://doi.org/10.1158/0008-5472.CAN-18-1924
http://hdl.handle.net/10459.1/65789
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1158/0008-5472.CAN-18-1924
Cancer Research, 2019, vol. 79, núm. 8, p. 1857-1868
dc.rights.none.fl_str_mv (c) American Association for Cancer Research, 2019
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Association for Cancer Research, 2019
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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