title: Vinca alkaloid drugs promote stress-induced translational repression and stress granule formation.
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.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.|Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Szaflarski
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Fay
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Kedersha
authors.affiliation: Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Zabel
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Anderson
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.|The Broad Institute of Harvard and M.I.T., Cambridge, MA, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Ivanov
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000187:drug effects* / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D034622:RNA Interference; D013312:Stress, Physiological / Q000187:drug effects*; D014748:Vinca Alkaloids / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D014748:Vinca Alkaloids; D014750:Vincristine
keywords: cancer; chemotherapy; stress granules; stress response; translation initiation