Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma
- Autores
- Yael, Kusne; Carrera Silva, Eugenio Antonio; Perry, Anthony S.; Rushing, Elisabeth J.; Mandell, Edward K.; Dietrich, Justin D.; Errasti, Andrea Emilse; Gibbs, Daniel; Berens, Michael E.; Loftus, Joseph C.; Hulme, Christopher; Yang, Weiwei; Lu, Zhimin; Aldape, Kenneth; Sanai, Nader; Rothlin, Carla V.; Ghosh, Sourav
- Año de publicación
- 2014
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-alpha (TNFa) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFa-dependent activation of the transcription factor nuclear factor kappa B (NF-kB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.
Fil: Yael, Kusne. Arizona State University; Estados Unidos
Fil: Carrera Silva, Eugenio Antonio. University of Yale. School of Medicine; Estados Unidos
Fil: Perry, Anthony S.. Banner MD Anderson Cancer Center; Estados Unidos
Fil: Rushing, Elisabeth J.. Armed Forces Institute of Pathology; Estados Unidos
Fil: Mandell, Edward K.. University of Yale; Estados Unidos
Fil: Dietrich, Justin D.. University of Arizona; Estados Unidos
Fil: Errasti, Andrea Emilse. University of Yale. School of Medicine; Estados Unidos. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina
Fil: Gibbs, Daniel. University of California; Estados Unidos
Fil: Berens, Michael E.. Translational Genomics Research Institute; Estados Unidos
Fil: Loftus, Joseph C.. Mayo Clinic Cancer Center; Estados Unidos
Fil: Hulme, Christopher. University of Arizona; Estados Unidos
Fil: Yang, Weiwei. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Lu, Zhimin. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Aldape, Kenneth. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Sanai, Nader. Arizona State University; Estados Unidos
Fil: Rothlin, Carla V.. University of Yale. School of Medicine; Estados Unidos
Fil: Ghosh, Sourav. Arizona State University; Estados Unidos. University of Yale. School of Medicine; Estados Unidos - Materia
-
aPKC
EGFR
TNFα
glioblastoma - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/112908
Ver los metadatos del registro completo
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Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastomaYael, KusneCarrera Silva, Eugenio AntonioPerry, Anthony S.Rushing, Elisabeth J.Mandell, Edward K.Dietrich, Justin D.Errasti, Andrea EmilseGibbs, DanielBerens, Michael E.Loftus, Joseph C.Hulme, ChristopherYang, WeiweiLu, ZhiminAldape, KennethSanai, NaderRothlin, Carla V.Ghosh, SouravaPKCEGFRTNFαglioblastomahttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-alpha (TNFa) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFa-dependent activation of the transcription factor nuclear factor kappa B (NF-kB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.Fil: Yael, Kusne. Arizona State University; Estados UnidosFil: Carrera Silva, Eugenio Antonio. University of Yale. School of Medicine; Estados UnidosFil: Perry, Anthony S.. Banner MD Anderson Cancer Center; Estados UnidosFil: Rushing, Elisabeth J.. Armed Forces Institute of Pathology; Estados UnidosFil: Mandell, Edward K.. University of Yale; Estados UnidosFil: Dietrich, Justin D.. University of Arizona; Estados UnidosFil: Errasti, Andrea Emilse. University of Yale. School of Medicine; Estados Unidos. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Gibbs, Daniel. University of California; Estados UnidosFil: Berens, Michael E.. Translational Genomics Research Institute; Estados UnidosFil: Loftus, Joseph C.. Mayo Clinic Cancer Center; Estados UnidosFil: Hulme, Christopher. University of Arizona; Estados UnidosFil: Yang, Weiwei. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Lu, Zhimin. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Aldape, Kenneth. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Sanai, Nader. Arizona State University; Estados UnidosFil: Rothlin, Carla V.. University of Yale. School of Medicine; Estados UnidosFil: Ghosh, Sourav. Arizona State University; Estados Unidos. University of Yale. School of Medicine; Estados UnidosAmerican Association for the Advancement of Science2014-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/112908Yael, Kusne; Carrera Silva, Eugenio Antonio; Perry, Anthony S.; Rushing, Elisabeth J.; Mandell, Edward K.; et al.; Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma; American Association for the Advancement of Science; Science Signaling; 7; 338; 8-2014; ra75-ra751937-9145CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486020/info:eu-repo/semantics/altIdentifier/doi/10.1126%2Fscisignal.2005196info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:44:42Zoai:ri.conicet.gov.ar:11336/112908instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:44:43.063CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma |
| title |
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma |
| spellingShingle |
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma Yael, Kusne aPKC EGFR TNFα glioblastoma |
| title_short |
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma |
| title_full |
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma |
| title_fullStr |
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma |
| title_full_unstemmed |
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma |
| title_sort |
Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma |
| dc.creator.none.fl_str_mv |
Yael, Kusne Carrera Silva, Eugenio Antonio Perry, Anthony S. Rushing, Elisabeth J. Mandell, Edward K. Dietrich, Justin D. Errasti, Andrea Emilse Gibbs, Daniel Berens, Michael E. Loftus, Joseph C. Hulme, Christopher Yang, Weiwei Lu, Zhimin Aldape, Kenneth Sanai, Nader Rothlin, Carla V. Ghosh, Sourav |
| author |
Yael, Kusne |
| author_facet |
Yael, Kusne Carrera Silva, Eugenio Antonio Perry, Anthony S. Rushing, Elisabeth J. Mandell, Edward K. Dietrich, Justin D. Errasti, Andrea Emilse Gibbs, Daniel Berens, Michael E. Loftus, Joseph C. Hulme, Christopher Yang, Weiwei Lu, Zhimin Aldape, Kenneth Sanai, Nader Rothlin, Carla V. Ghosh, Sourav |
| author_role |
author |
| author2 |
Carrera Silva, Eugenio Antonio Perry, Anthony S. Rushing, Elisabeth J. Mandell, Edward K. Dietrich, Justin D. Errasti, Andrea Emilse Gibbs, Daniel Berens, Michael E. Loftus, Joseph C. Hulme, Christopher Yang, Weiwei Lu, Zhimin Aldape, Kenneth Sanai, Nader Rothlin, Carla V. Ghosh, Sourav |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
aPKC EGFR TNFα glioblastoma |
| topic |
aPKC EGFR TNFα glioblastoma |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
| dc.description.none.fl_txt_mv |
Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-alpha (TNFa) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFa-dependent activation of the transcription factor nuclear factor kappa B (NF-kB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy. Fil: Yael, Kusne. Arizona State University; Estados Unidos Fil: Carrera Silva, Eugenio Antonio. University of Yale. School of Medicine; Estados Unidos Fil: Perry, Anthony S.. Banner MD Anderson Cancer Center; Estados Unidos Fil: Rushing, Elisabeth J.. Armed Forces Institute of Pathology; Estados Unidos Fil: Mandell, Edward K.. University of Yale; Estados Unidos Fil: Dietrich, Justin D.. University of Arizona; Estados Unidos Fil: Errasti, Andrea Emilse. University of Yale. School of Medicine; Estados Unidos. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Gibbs, Daniel. University of California; Estados Unidos Fil: Berens, Michael E.. Translational Genomics Research Institute; Estados Unidos Fil: Loftus, Joseph C.. Mayo Clinic Cancer Center; Estados Unidos Fil: Hulme, Christopher. University of Arizona; Estados Unidos Fil: Yang, Weiwei. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Lu, Zhimin. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Aldape, Kenneth. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Sanai, Nader. Arizona State University; Estados Unidos Fil: Rothlin, Carla V.. University of Yale. School of Medicine; Estados Unidos Fil: Ghosh, Sourav. Arizona State University; Estados Unidos. University of Yale. School of Medicine; Estados Unidos |
| description |
Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-alpha (TNFa) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFa-dependent activation of the transcription factor nuclear factor kappa B (NF-kB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy. |
| publishDate |
2014 |
| dc.date.none.fl_str_mv |
2014-08 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
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article |
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publishedVersion |
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http://hdl.handle.net/11336/112908 Yael, Kusne; Carrera Silva, Eugenio Antonio; Perry, Anthony S.; Rushing, Elisabeth J.; Mandell, Edward K.; et al.; Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma; American Association for the Advancement of Science; Science Signaling; 7; 338; 8-2014; ra75-ra75 1937-9145 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/112908 |
| identifier_str_mv |
Yael, Kusne; Carrera Silva, Eugenio Antonio; Perry, Anthony S.; Rushing, Elisabeth J.; Mandell, Edward K.; et al.; Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFa in glioblastoma; American Association for the Advancement of Science; Science Signaling; 7; 338; 8-2014; ra75-ra75 1937-9145 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
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