Autophagy-Dependent Survival of Mutant B-Raf Melanoma Cells Selected for Resistance to Apoptosis Induced by Inhibitors against Oncogenic B-Raf
Biomolecules & Therapeutics
;
: 114-120, 2013.
Artigo
em Inglês
| WPRIM
| ID: wpr-201023
ABSTRACT
Most patients with mutant B-Raf melanomas respond to inhibitors of oncogenic B-Raf but resistance eventually emerges. To better understand the mechanisms that determine the long-term responses of mutant B-Raf melanoma cells to B-Raf inhibitor, we used chronic selection to establish B-Raf (V600E) melanoma clones with acquired resistance to the new oncogenic B-Raf inhibitor UI-152. Whereas the parental A375P cells were highly sensitive to UI-152 (IC5020 microM). Immunofluorescence analysis indicated the absence of an increase in the levels of P-glycoprotein multidrug resistance (MDR) transporter in A375P/Mdr cells, suggesting that resistance was not attributable to P-glycoprotein overexpression. In UI-152-sensitive A375P cells, the anti-proliferative activity of UI-152 appeared to be due to cell-cycle arrest at G0/G1 with the induction of apoptosis. However, we found that A375P/Mdr cells were resistant to the apoptosis induced by UI-152. Interestingly, UI-152 preferentially induced autophagy in A375P/Mdr cells but not in A375P cells, as determined by GFP-LC3 puncta/cell counts. Further, autophagy inhibition with 3-methyladenine (3-MA) partially augmented growth inhibition of A375P/Mdr cells by UI-152, which implies that a high level of autophagy may protect UI-152-treated cells from undergoing growth inhibition. Together, our data implicate high rates of autophagy as a key mechanism of acquired resistance to the oncogenic B-Raf inhibitor, in support of clinical studies in which combination therapy with autophagy targeted drugs is being designed to overcome resistance.
Texto completo:
DisponíveL
Índice:
WPRIM (Pacífico Ocidental)
Assunto principal:
Pais
/
Autofagia
/
Resistência a Medicamentos
/
Imunofluorescência
/
Células Clonais
/
Apoptose
/
Membro 1 da Subfamília B de Cassetes de Ligação de ATP
/
Resistência a Múltiplos Medicamentos
/
Pontos de Checagem do Ciclo Celular
/
Melanoma
Limite:
Humanos
Idioma:
Inglês
Revista:
Biomolecules & Therapeutics
Ano de publicação:
2013
Tipo de documento:
Artigo
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