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Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma

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Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma

dc.contributor.author	Estrela Arigüel, José María
dc.contributor.author	Salvador Palmer, M. del Rosario
dc.contributor.author	Marchio, Patricia
dc.contributor.author	Valles Martí, Lilián Soraya
dc.contributor.author	López-Blanch, Rafael
dc.contributor.author	Rivera, Pilar
dc.contributor.author	Benlloch García, María
dc.contributor.author	Alcácer, Javier
dc.contributor.author	Pérez, Carlos L
dc.contributor.author	Pellicer, José A
dc.contributor.author	Obrador Plá, Elena
dc.date.accessioned	2020-04-21T08:06:44Z
dc.date.available	2020-04-21T08:06:44Z
dc.date.issued	2019
dc.identifier.citation	Estrela Arigüel, José María Salvador Palmer, M. del Rosario Marchio, Patricia Valles Martí, Lilian Soraya López-Blanch, Rafael Rivera, Pilar Benlloch García, María Alcácer, Javier Pérez, Carlos L Pellicer, José A Obrador Plá, Elena 2019 Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma American Journal Of Cancer Research 9 12 2580 2598
dc.identifier.uri	https://hdl.handle.net/10550/73941
dc.description.abstract	Clinical applications of glucocorticoids (GC) in Oncology are dependent on their pro-apoptotic action to treat lymphoproliferative cancers, and to alleviate side effects induced by chemotherapy and/or radiotherapy. However, the mechanism(s) by which GC may also promote tumor progression remains unclear. GC receptor (GR) knockdown decreases the antioxidant protection of highly metastatic B16-F10 melanoma cells. We hypothesize that a GR antagonist (RU486, mifepristone) could increase the efficacy of BRAF-related therapy in BRAFV600E-mutated metastatic melanoma. In vivo formed spontaneous skin tumors were reinoculated into nude mice to expand the metastases of different human BRAFV600E melanoma cells. The GR content of melanoma cell lines was measured by [3H]-labeled ligand binding assay. Nuclear Nrf2 and its transcription activity was investigated by RT-PCR, western blotting, and by measuring Nrf2- and redox state-related enzyme activities and metabolites. GR knockdown was achieved using lentivirus, and GR overexpression by transfection with the NR3C1 plasmid. shRNA-induced selective Bcl-xL, Mcl-1, AKT1 or NF-κB/p65 depletion was used to test the efficacy of vemurafenib (VMF) and RU486 against BRAFV600E-mutated metastatic melanoma. During early progression of skin melanoma metastases, RU486 and VMF induced a drastic metastases regression. However, treatment at an advanced stage of growth demonstrated the development of resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of specific proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in our experimental models). We found that melanoma resistance is decreased if AKT and NF-κB signaling pathways are blocked. Our results highlight mechanisms by which metastatic melanoma cells adapt to survive.
dc.language.iso	eng
dc.relation.ispartof	American Journal Of Cancer Research, 2019, vol. 9, num. 12, p. 2580-2598
dc.subject	Melanoma
dc.title	Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma
dc.type	journal article	es_ES
dc.date.updated	2020-04-21T08:06:45Z
dc.identifier.idgrec	135721
dc.rights.accessRights	open access	es_ES