PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation

Autores
Villegas, Santiago Nahuel; Gombos, Rita; García López, Lucia; Gutiérrez Pérez, Irene; García Castillo, Jesús; Vallejo, Diana Marcela; Da Ros, Vanina Gabriela; Ballesta Illán, Esther; Mihály, József; Dominguez, Maria
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt-induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.
Fil: Villegas, Santiago Nahuel. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Gombos, Rita. Magyar Tudományos Akadémia; Hungría
Fil: García López, Lucia. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Gutiérrez Pérez, Irene. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: García Castillo, Jesús. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Vallejo, Diana Marcela. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Da Ros, Vanina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Ballesta Illán, Esther. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Mihály, József. Magyar Tudományos Akadémia; Hungría
Fil: Dominguez, Maria. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Materia
BW B70C
CANCER
CHEMICAL SCREEN
DROSOPHILA
INFLAMMATION
LOX
NOS
NOTCH
PTEN/PI3K/AKT
T-ALL
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/89506
Acceder
id CONICETDig_961980d5f5495a628da28af8ac0cc0f0
oai_identifier_str oai:ri.conicet.gov.ar:11336/89506
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammationVillegas, Santiago NahuelGombos, RitaGarcía López, LuciaGutiérrez Pérez, IreneGarcía Castillo, JesúsVallejo, Diana MarcelaDa Ros, Vanina GabrielaBallesta Illán, EstherMihály, JózsefDominguez, MariaBW B70CCANCERCHEMICAL SCREENDROSOPHILAINFLAMMATIONLOXNOSNOTCHPTEN/PI3K/AKTT-ALLhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt-induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.Fil: Villegas, Santiago Nahuel. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; EspañaFil: Gombos, Rita. Magyar Tudományos Akadémia; HungríaFil: García López, Lucia. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; EspañaFil: Gutiérrez Pérez, Irene. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; EspañaFil: García Castillo, Jesús. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; EspañaFil: Vallejo, Diana Marcela. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; EspañaFil: Da Ros, Vanina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ballesta Illán, Esther. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; EspañaFil: Mihály, József. Magyar Tudományos Akadémia; HungríaFil: Dominguez, Maria. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; EspañaElsevier B.V.2018-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/89506Villegas, Santiago Nahuel; Gombos, Rita; García López, Lucia; Gutiérrez Pérez, Irene; García Castillo, Jesús; et al.; PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation; Elsevier B.V.; Cell Reports; 22; 10; 3-2018; 2541-25492211-1247CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://linkinghub.elsevier.com/retrieve/pii/S2211124718302304info:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2018.02.049info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-03-31T14:46:23Zoai:ri.conicet.gov.ar:11336/89506instacron: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:34982026-03-31 14:46:24.141CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation
title PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation
spellingShingle PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation
Villegas, Santiago Nahuel
BW B70C
CANCER
CHEMICAL SCREEN
DROSOPHILA
INFLAMMATION
LOX
NOS
NOTCH
PTEN/PI3K/AKT
T-ALL
title_short PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation
title_full PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation
title_fullStr PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation
title_full_unstemmed PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation
title_sort PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation
dc.creator.none.fl_str_mv Villegas, Santiago Nahuel
Gombos, Rita
García López, Lucia
Gutiérrez Pérez, Irene
García Castillo, Jesús
Vallejo, Diana Marcela
Da Ros, Vanina Gabriela
Ballesta Illán, Esther
Mihály, József
Dominguez, Maria
author Villegas, Santiago Nahuel
author_facet Villegas, Santiago Nahuel
Gombos, Rita
García López, Lucia
Gutiérrez Pérez, Irene
García Castillo, Jesús
Vallejo, Diana Marcela
Da Ros, Vanina Gabriela
Ballesta Illán, Esther
Mihály, József
Dominguez, Maria
author_role author
author2 Gombos, Rita
García López, Lucia
Gutiérrez Pérez, Irene
García Castillo, Jesús
Vallejo, Diana Marcela
Da Ros, Vanina Gabriela
Ballesta Illán, Esther
Mihály, József
Dominguez, Maria
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv BW B70C
CANCER
CHEMICAL SCREEN
DROSOPHILA
INFLAMMATION
LOX
NOS
NOTCH
PTEN/PI3K/AKT
T-ALL
topic BW B70C
CANCER
CHEMICAL SCREEN
DROSOPHILA
INFLAMMATION
LOX
NOS
NOTCH
PTEN/PI3K/AKT
T-ALL
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt-induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.
Fil: Villegas, Santiago Nahuel. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Gombos, Rita. Magyar Tudományos Akadémia; Hungría
Fil: García López, Lucia. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Gutiérrez Pérez, Irene. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: García Castillo, Jesús. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Vallejo, Diana Marcela. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Da Ros, Vanina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Ballesta Illán, Esther. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
Fil: Mihály, József. Magyar Tudományos Akadémia; Hungría
Fil: Dominguez, Maria. Consejo Superior de Investigaciones Científicas. Instituto de Neurociencia de Alicante; España
description The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt-induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.
publishDate 2018
dc.date.none.fl_str_mv 2018-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/89506
Villegas, Santiago Nahuel; Gombos, Rita; García López, Lucia; Gutiérrez Pérez, Irene; García Castillo, Jesús; et al.; PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation; Elsevier B.V.; Cell Reports; 22; 10; 3-2018; 2541-2549
2211-1247
CONICET Digital
CONICET
url http://hdl.handle.net/11336/89506
identifier_str_mv Villegas, Santiago Nahuel; Gombos, Rita; García López, Lucia; Gutiérrez Pérez, Irene; García Castillo, Jesús; et al.; PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation; Elsevier B.V.; Cell Reports; 22; 10; 3-2018; 2541-2549
2211-1247
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://linkinghub.elsevier.com/retrieve/pii/S2211124718302304
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2018.02.049
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier B.V.
publisher.none.fl_str_mv Elsevier B.V.
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.720982

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