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

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

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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, Lilian 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.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.rights.uri info:eu-repo/semantics/openAccess
dc.source 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.subject Melanoma
dc.title Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma
dc.type info:eu-repo/semantics/article
dc.date.updated 2020-04-21T08:06:45Z
dc.identifier.idgrec 135721

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