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

Witold Szaflarski; Marta M. Fay; Nancy Kedersha; Maciej Zabel; Paul Anderson; Pavel Ivanov

doi:10.18632/oncotarget.8728

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Research Papers:

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

Witold Szaflarski, Marta M. Fay, Nancy Kedersha, Maciej Zabel, Paul Anderson and Pavel Ivanov _

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Oncotarget. 2016; 7:30307-30322. https://doi.org/10.18632/oncotarget.8728

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Abstract

Witold Szaflarski1,2,3, Marta M. Fay1,2, Nancy Kedersha1,2, Maciej Zabel3, Paul Anderson1,2 and Pavel Ivanov1,2,4

1 Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, USA

2 Department of Medicine, Harvard Medical School, Boston, MA, USA

3 Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland

4 The Broad Institute of Harvard and M.I.T., Cambridge, MA, USA

Correspondence to:

Pavel Ivanov, email:

Keywords: chemotherapy, stress granules, translation initiation, stress response, cancer

Received: February 10, 2016 Accepted: March 31, 2016 Published: April 13, 2016

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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Research Papers:

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

Abstract