Vinca alkaloid drugs promote stress-induced translational repression and stress granule formation.
Oncotarget
; 7(21): 30307-22, 2016 May 24.
Article
em En
| MEDLINE
| ID: mdl-27083003
ABSTRACT
Resistance to chemotherapy drugs is a serious therapeutic problem and its underlying molecular mechanisms are complex. Stress granules (SGs), cytoplasmic ribonucleoprotein complexes assembled in cells exposed to stress, are implicated in various aspects of cancer cell metabolism and survival. SGs promote the survival of stressed cells by reprogramming gene expression and inhibiting pro-apoptotic signaling cascades. We show that the vinca alkaloid (VA) class of anti-neoplastic agents potently activates a SG-mediated stress response program. VAs inhibit translation initiation by simultaneous activation of eIF4E-BP1 and phosphorylation of eIF2α, causing polysome disassembly and SG assembly. VA-induced SGs contain canonical SG components but lack specific signaling molecules. Blocking VA-induced SG assembly by inactivating eIF4EBP1 or inhibiting eIF2α phosphorylation decreases cancer cell viability and promotes apoptosis. Our data describe previously unappreciated effects of VAs on cellular RNA metabolism and illuminate the roles of SGs in cancer cell survival.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Estresse Fisiológico
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Biossíntese de Proteínas
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Alcaloides de Vinca
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Grânulos Citoplasmáticos
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article