Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax

The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis.The mammalian target of rapamycin (mTOR)is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR existsin two complexe...

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Autores: Espona Fiedler, Margarita, Soto Cerrato, Vanessa, Hosseini, Seyed Ali, Lizcano, José Miguel, Guallar, Victor, Quesada, Roberto, Gao, T., Pérez Tomás, Ricardo E.
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2012
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:2445/46036
Acceso en línea:https://hdl.handle.net/2445/46036
Access Level:acceso abierto
Palabra clave:Proteïnes quinases
Melanoma
Assaigs clínics
Terapèutica
Protein kinases
Clinical trials
Therapeutics
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spelling Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclaxEspona Fiedler, MargaritaSoto Cerrato, VanessaHosseini, Seyed AliLizcano, José MiguelGuallar, VictorQuesada, RobertoGao, T.Pérez Tomás, Ricardo E.Proteïnes quinasesMelanomaAssaigs clínicsTerapèuticaProtein kinasesMelanomaClinical trialsTherapeuticsThe PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis.The mammalian target of rapamycin (mTOR)is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR existsin two complexes, mTORC1 and mTORC2.Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modeling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.Elsevier B.V.2013201320122013info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion8 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/46036Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame: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: 10.1016/j.bcp.2011.11.027Biochemical Pharmacology, 2012, vol. 83, num. 4, p. 489-496http://dx.doi.org/10.1016/j.bcp.2011.11.027(c) Elsevier B.V., 2012info:eu-repo/semantics/openAccessoai:recercat.cat:2445/460362026-05-29T05:05:01Z
dc.title.none.fl_str_mv Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
title Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
spellingShingle Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
Espona Fiedler, Margarita
Proteïnes quinases
Melanoma
Assaigs clínics
Terapèutica
Protein kinases
Melanoma
Clinical trials
Therapeutics
title_short Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
title_full Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
title_fullStr Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
title_full_unstemmed Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
title_sort Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs.obatoclax
dc.creator.none.fl_str_mv Espona Fiedler, Margarita
Soto Cerrato, Vanessa
Hosseini, Seyed Ali
Lizcano, José Miguel
Guallar, Victor
Quesada, Roberto
Gao, T.
Pérez Tomás, Ricardo E.
author Espona Fiedler, Margarita
author_facet Espona Fiedler, Margarita
Soto Cerrato, Vanessa
Hosseini, Seyed Ali
Lizcano, José Miguel
Guallar, Victor
Quesada, Roberto
Gao, T.
Pérez Tomás, Ricardo E.
author_role author
author2 Soto Cerrato, Vanessa
Hosseini, Seyed Ali
Lizcano, José Miguel
Guallar, Victor
Quesada, Roberto
Gao, T.
Pérez Tomás, Ricardo E.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïnes quinases
Melanoma
Assaigs clínics
Terapèutica
Protein kinases
Melanoma
Clinical trials
Therapeutics
topic Proteïnes quinases
Melanoma
Assaigs clínics
Terapèutica
Protein kinases
Melanoma
Clinical trials
Therapeutics
description The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis.The mammalian target of rapamycin (mTOR)is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR existsin two complexes, mTORC1 and mTORC2.Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modeling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.
publishDate 2012
dc.date.none.fl_str_mv 2012
2013
2013
2013
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://hdl.handle.net/2445/46036
url https://hdl.handle.net/2445/46036
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: 10.1016/j.bcp.2011.11.027
Biochemical Pharmacology, 2012, vol. 83, num. 4, p. 489-496
http://dx.doi.org/10.1016/j.bcp.2011.11.027
dc.rights.none.fl_str_mv (c) Elsevier B.V., 2012
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Elsevier B.V., 2012
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 8 p.
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 Articles publicats en revistes (Patologia i Terapèutica Experimental)
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 15,811543

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