Vinca alkaloid drugs promote stress-induced translational repression and stress granule formation

被引：45

作者：

Szaflarski, Witold ^{[1
,2
,3
]}

Fay, Marta M. ^{[1
,2
]}

Kedersha, Nancy ^{[1
,2
]}

Zabel, Maciej ^{[3
]}

Anderson, Paul ^{[1
,2
]}

Ivanov, Pavel ^{[1
,2
,4
]}

机构：

[1] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[3] Poznan Univ Med Sci, Dept Histol & Embryol, Poznan, Poland

[4] Broad Inst Harvard & MIT, Cambridge, MA USA

来源：

ONCOTARGET | 2016年 / 7卷 / 21期

关键词：

chemotherapy; stress granules; translation initiation; stress response; cancer; UNFOLDED PROTEIN RESPONSE; PROCESSING BODIES; GLUCOSE-HOMEOSTASIS; GENE-EXPRESSION; CELL-SIZE; INITIATION; PHOSPHORYLATION; RNA; APOPTOSIS; SURVIVAL;

D O I：

10.18632/oncotarget.8728

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 eIF2 alpha, 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 eIF2 alpha 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.

引用

页码：30307 / 30322

页数：16

共 48 条

[1] Sorafenib, a multikinase inhibitor, induces formation of stress granules in hepatocarcinoma cells [J].