A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis

Autores
Zadra, Giorgia; Photopoulos, Cornelia; Tyekucheva, Svitlana; Heidari, Pedram; Weng, Qing Ping; Fedele, Giuseppe; Liu, Hong; Scaglia, Natalia; Priolo, Carmen; Sicinska, Ewa; Mahmood, Umar; Signoretti, Sabina; Birnberg, Neal; Loda, Massimo
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
5´AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63-78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63-78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.
Fil: Zadra, Giorgia. Harvard Medical School; Estados Unidos
Fil: Photopoulos, Cornelia. Harvard Medical School; Estados Unidos
Fil: Tyekucheva, Svitlana. Harvard University. Harvard School of Public Health; Estados Unidos. Harvard Medical School; Estados Unidos
Fil: Heidari, Pedram. Massachusetts General Hospital; Estados Unidos
Fil: Weng, Qing Ping. Mercury Pharmaceuticals; Estados Unidos
Fil: Fedele, Giuseppe. Harvard Medical School; Estados Unidos
Fil: Liu, Hong. Mercury Pharmaceuticals; Estados Unidos
Fil: Scaglia, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina. Harvard Medical School; Estados Unidos
Fil: Priolo, Carmen. Harvard Medical School; Estados Unidos
Fil: Sicinska, Ewa. Harvard Medical School; Estados Unidos
Fil: Mahmood, Umar. Massachusetts General Hospital; Estados Unidos
Fil: Signoretti, Sabina. Harvard Medical School; Estados Unidos
Fil: Birnberg, Neal. Mercury Pharmaceuticals; Estados Unidos
Fil: Loda, Massimo. Harvard Medical School; Estados Unidos. King’s College London; Reino Unido. The Broad Institute; Estados Unidos
Materia
AMPK DIRECT ACTIVATION
ANDROGEN SIGNALING INHIBITORS
DE NOVO LIPOGENESIS
PROSTATE CANCER
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/101867
Acceder
id CONICETDig_97896dac2af9721ca1ee7d45cd013374
oai_identifier_str oai:ri.conicet.gov.ar:11336/101867
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesisZadra, GiorgiaPhotopoulos, CorneliaTyekucheva, SvitlanaHeidari, PedramWeng, Qing PingFedele, GiuseppeLiu, HongScaglia, NataliaPriolo, CarmenSicinska, EwaMahmood, UmarSignoretti, SabinaBirnberg, NealLoda, MassimoAMPK DIRECT ACTIVATIONANDROGEN SIGNALING INHIBITORSDE NOVO LIPOGENESISPROSTATE CANCERhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/15´AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63-78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63-78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.Fil: Zadra, Giorgia. Harvard Medical School; Estados UnidosFil: Photopoulos, Cornelia. Harvard Medical School; Estados UnidosFil: Tyekucheva, Svitlana. Harvard University. Harvard School of Public Health; Estados Unidos. Harvard Medical School; Estados UnidosFil: Heidari, Pedram. Massachusetts General Hospital; Estados UnidosFil: Weng, Qing Ping. Mercury Pharmaceuticals; Estados UnidosFil: Fedele, Giuseppe. Harvard Medical School; Estados UnidosFil: Liu, Hong. Mercury Pharmaceuticals; Estados UnidosFil: Scaglia, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina. Harvard Medical School; Estados UnidosFil: Priolo, Carmen. Harvard Medical School; Estados UnidosFil: Sicinska, Ewa. Harvard Medical School; Estados UnidosFil: Mahmood, Umar. Massachusetts General Hospital; Estados UnidosFil: Signoretti, Sabina. Harvard Medical School; Estados UnidosFil: Birnberg, Neal. Mercury Pharmaceuticals; Estados UnidosFil: Loda, Massimo. Harvard Medical School; Estados Unidos. King’s College London; Reino Unido. The Broad Institute; Estados UnidosWiley Blackwell Publishing, Inc2014-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/101867Zadra, Giorgia; Photopoulos, Cornelia; Tyekucheva, Svitlana; Heidari, Pedram; Weng, Qing Ping; et al.; A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis; Wiley Blackwell Publishing, Inc; Embo Molecular Medicine; 6; 4; 2-2014; 519-5381757-46761757-4684CONICET DigitalCONICETengCorregido en https://doi.org/10.15252/emmm.201470070info:eu-repo/semantics/altIdentifier/doi/10.1002/emmm.201302734info:eu-repo/semantics/altIdentifier/url/https://www.embopress.org/doi/full/10.1002/emmm.201302734info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:42:23Zoai:ri.conicet.gov.ar:11336/101867instacron: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:34982025-09-29 09:42:23.23CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
title A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
spellingShingle A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
Zadra, Giorgia
AMPK DIRECT ACTIVATION
ANDROGEN SIGNALING INHIBITORS
DE NOVO LIPOGENESIS
PROSTATE CANCER
title_short A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
title_full A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
title_fullStr A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
title_full_unstemmed A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
title_sort A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis
dc.creator.none.fl_str_mv Zadra, Giorgia
Photopoulos, Cornelia
Tyekucheva, Svitlana
Heidari, Pedram
Weng, Qing Ping
Fedele, Giuseppe
Liu, Hong
Scaglia, Natalia
Priolo, Carmen
Sicinska, Ewa
Mahmood, Umar
Signoretti, Sabina
Birnberg, Neal
Loda, Massimo
author Zadra, Giorgia
author_facet Zadra, Giorgia
Photopoulos, Cornelia
Tyekucheva, Svitlana
Heidari, Pedram
Weng, Qing Ping
Fedele, Giuseppe
Liu, Hong
Scaglia, Natalia
Priolo, Carmen
Sicinska, Ewa
Mahmood, Umar
Signoretti, Sabina
Birnberg, Neal
Loda, Massimo
author_role author
author2 Photopoulos, Cornelia
Tyekucheva, Svitlana
Heidari, Pedram
Weng, Qing Ping
Fedele, Giuseppe
Liu, Hong
Scaglia, Natalia
Priolo, Carmen
Sicinska, Ewa
Mahmood, Umar
Signoretti, Sabina
Birnberg, Neal
Loda, Massimo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AMPK DIRECT ACTIVATION
ANDROGEN SIGNALING INHIBITORS
DE NOVO LIPOGENESIS
PROSTATE CANCER
topic AMPK DIRECT ACTIVATION
ANDROGEN SIGNALING INHIBITORS
DE NOVO LIPOGENESIS
PROSTATE CANCER
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 5´AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63-78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63-78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.
Fil: Zadra, Giorgia. Harvard Medical School; Estados Unidos
Fil: Photopoulos, Cornelia. Harvard Medical School; Estados Unidos
Fil: Tyekucheva, Svitlana. Harvard University. Harvard School of Public Health; Estados Unidos. Harvard Medical School; Estados Unidos
Fil: Heidari, Pedram. Massachusetts General Hospital; Estados Unidos
Fil: Weng, Qing Ping. Mercury Pharmaceuticals; Estados Unidos
Fil: Fedele, Giuseppe. Harvard Medical School; Estados Unidos
Fil: Liu, Hong. Mercury Pharmaceuticals; Estados Unidos
Fil: Scaglia, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina. Harvard Medical School; Estados Unidos
Fil: Priolo, Carmen. Harvard Medical School; Estados Unidos
Fil: Sicinska, Ewa. Harvard Medical School; Estados Unidos
Fil: Mahmood, Umar. Massachusetts General Hospital; Estados Unidos
Fil: Signoretti, Sabina. Harvard Medical School; Estados Unidos
Fil: Birnberg, Neal. Mercury Pharmaceuticals; Estados Unidos
Fil: Loda, Massimo. Harvard Medical School; Estados Unidos. King’s College London; Reino Unido. The Broad Institute; Estados Unidos
description 5´AMP-activated kinase (AMPK) constitutes a hub for cellular metabolic and growth control, thus representing an ideal therapeutic target for prostate cancers (PCas) characterized by increased lipogenesis and activation of mTORC1 pathway. However, whether AMPK activation itself is sufficient to block cancer cell growth remains to be determined. A small molecule screening was performed and identified MT 63-78, a specific and potent direct AMPK activator. Here, we show that direct activation of AMPK inhibits PCa cell growth in androgen sensitive and castration resistant PCa (CRPC) models, induces mitotic arrest, and apoptosis. In vivo, AMPK activation is sufficient to reduce PCa growth, whereas the allelic loss of its catalytic subunits fosters PCa development. Importantly, despite mTORC1 blockade, the suppression of de novo lipogenesis is the underpinning mechanism responsible for AMPK-mediated PCa growth inhibition, suggesting AMPK as a therapeutic target especially for lipogenesis-driven PCas. Finally, we demonstrate that MT 63-78 enhances the growth inhibitory effect of AR signaling inhibitors MDV3100 and abiraterone. This study thus provides a rationale for their combined use in CRPC treatment.
publishDate 2014
dc.date.none.fl_str_mv 2014-02
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/11336/101867
Zadra, Giorgia; Photopoulos, Cornelia; Tyekucheva, Svitlana; Heidari, Pedram; Weng, Qing Ping; et al.; A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis; Wiley Blackwell Publishing, Inc; Embo Molecular Medicine; 6; 4; 2-2014; 519-538
1757-4676
1757-4684
CONICET Digital
CONICET
url http://hdl.handle.net/11336/101867
identifier_str_mv Zadra, Giorgia; Photopoulos, Cornelia; Tyekucheva, Svitlana; Heidari, Pedram; Weng, Qing Ping; et al.; A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis; Wiley Blackwell Publishing, Inc; Embo Molecular Medicine; 6; 4; 2-2014; 519-538
1757-4676
1757-4684
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Corregido en https://doi.org/10.15252/emmm.201470070
info:eu-repo/semantics/altIdentifier/doi/10.1002/emmm.201302734
info:eu-repo/semantics/altIdentifier/url/https://www.embopress.org/doi/full/10.1002/emmm.201302734
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
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
_version_ 1844613334991634432
score 13.070432

Publicaciones similares