Vinca Alkaloid Drugs Promote Stress-induced Translational Repression and Stress Granule Formation

Overview

Journal Oncotarget

Specialty Oncology

Date 2016 Apr 16

PMID 27083003

Citations 35

Authors

Witold Szaflarski

Marta M Fay

Nancy Kedersha

Maciej Zabel

Paul Anderson

Pavel Ivanov

Affiliations

Soon will be listed here.

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.

Citing Articles

Suppression of stress granule formation is a vulnerability imposed by mutant p53.

Thoenen E, Ranjan A, Parrales A, Nishikawa S, Dixon D, Oka S Nat Commun. 2025; 16(1):2365.

PMID: 40064891 PMC: 11894096. DOI: 10.1038/s41467-025-57539-6.

Biomolecular condensates and disease pathogenesis.

Ruan K, Bai G, Fang Y, Li D, Li T, Liu X Sci China Life Sci. 2024; 67(9):1792-1832.

PMID: 39037698 DOI: 10.1007/s11427-024-2661-3.

Stress granule-mediated sequestration of EGR1 mRNAs correlates with lomustine-induced cell death prevention.

Lesniczak-Staszak M, Pietras P, Rucinski M, Johnston R, Sowinski M, Andrzejewska M J Cell Sci. 2024; 137(12).

PMID: 38940347 PMC: 11234381. DOI: 10.1242/jcs.261825.

Stress Granule Core Protein-Derived Peptides Inhibit Assembly of Stress Granules and Improve Sorafenib Sensitivity in Cancer Cells.

Li J, Zhang Y, Gu J, Zhou Y, Liu J, Cui H Molecules. 2024; 29(9).

PMID: 38731625 PMC: 11085366. DOI: 10.3390/molecules29092134.

HuR-positive stress granules: Potential targets for age-related osteoporosis.

Huai Y, Wang X, Mao W, Wang X, Zhao Y, Chu X Aging Cell. 2024; 23(3):e14053.

PMID: 38375951 PMC: 10928564. DOI: 10.1111/acel.14053.

References

Chernov K, Barbet A, Hamon L, Ovchinnikov L, Curmi P, Pastre D . Role of microtubules in stress granule assembly: microtubule dynamical instability favors the formation of micrometric stress granules in cells. J Biol Chem. 2009; 284(52):36569-36580. PMC: 2794772. DOI: 10.1074/jbc.M109.042879. View

Avivar-Valderas A, Salas E, Bobrovnikova-Marjon E, Diehl J, Nagi C, Debnath J . PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment. Mol Cell Biol. 2011; 31(17):3616-29. PMC: 3165554. DOI: 10.1128/MCB.05164-11. View

Cullinan S, Diehl J . Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. Int J Biochem Cell Biol. 2005; 38(3):317-32. DOI: 10.1016/j.biocel.2005.09.018. View

Damgaard C, Lykke-Andersen J . Translational coregulation of 5'TOP mRNAs by TIA-1 and TIAR. Genes Dev. 2011; 25(19):2057-68. PMC: 3197204. DOI: 10.1101/gad.17355911. View

Adjibade P, St-Sauveur V, Quevillon Huberdeau M, Fournier M, Savard A, Coudert L . Sorafenib, a multikinase inhibitor, induces formation of stress granules in hepatocarcinoma cells. Oncotarget. 2015; 6(41):43927-43. PMC: 4791277. DOI: 10.18632/oncotarget.5980. View

Donnelly N, Gorman A, Gupta S, Samali A . The eIF2α kinases: their structures and functions. Cell Mol Life Sci. 2013; 70(19):3493-511. PMC: 11113696. DOI: 10.1007/s00018-012-1252-6. View

Ruvinsky I, Sharon N, Lerer T, Cohen H, Stolovich-Rain M, Nir T . Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev. 2005; 19(18):2199-211. PMC: 1221890. DOI: 10.1101/gad.351605. View

Kedersha N, Anderson P . Mammalian stress granules and processing bodies. Methods Enzymol. 2007; 431:61-81. DOI: 10.1016/S0076-6879(07)31005-7. View

Fujimura K, Sasaki A, Anderson P . Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules. Nucleic Acids Res. 2012; 40(16):8099-110. PMC: 3439927. DOI: 10.1093/nar/gks566. View

10.

Harding H, Zhang Y, Bertolotti A, Zeng H, Ron D . Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell. 2000; 5(5):897-904. DOI: 10.1016/s1097-2765(00)80330-5. View

11.

Bordeleau M, Robert F, Gerard B, Lindqvist L, Chen S, Wendel H . Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008; 118(7):2651-60. PMC: 2423864. DOI: 10.1172/JCI34753. View

12.

Mendoza M, Er E, Blenis J . The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011; 36(6):320-8. PMC: 3112285. DOI: 10.1016/j.tibs.2011.03.006. View

13.

Ivanov P, Chudinova E, Nadezhdina E . Disruption of microtubules inhibits cytoplasmic ribonucleoprotein stress granule formation. Exp Cell Res. 2003; 290(2):227-33. DOI: 10.1016/s0014-4827(03)00290-8. View

14.

McEwen E, Kedersha N, Song B, Scheuner D, Gilks N, Han A . Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J Biol Chem. 2005; 280(17):16925-33. DOI: 10.1074/jbc.M412882200. View

15.

Li J, Xie D . RACK1, a versatile hub in cancer. Oncogene. 2014; 34(15):1890-8. DOI: 10.1038/onc.2014.127. View

16.

Dostal V, Libusova L . Microtubule drugs: action, selectivity, and resistance across the kingdoms of life. Protoplasma. 2014; 251(5):991-1005. DOI: 10.1007/s00709-014-0633-0. View

17.

Mason T, Kolobova E, Liu J, Roland J, Chiang C, Goldenring J . Darinaparsin is a multivalent chemotherapeutic which induces incomplete stress response with disruption of microtubules and Shh signaling. PLoS One. 2011; 6(11):e27699. PMC: 3216988. DOI: 10.1371/journal.pone.0027699. View

18.

Anderson P, Kedersha N . Stress granules. Curr Biol. 2009; 19(10):R397-8. DOI: 10.1016/j.cub.2009.03.013. View

19.

Cencic R, Robert F, Galicia-Vazquez G, Malina A, Ravindar K, Somaiah R . Modifying chemotherapy response by targeted inhibition of eukaryotic initiation factor 4A. Blood Cancer J. 2013; 3:e128. PMC: 3730203. DOI: 10.1038/bcj.2013.25. View

20.

Sun S . N-acetylcysteine, reactive oxygen species and beyond. Cancer Biol Ther. 2009; 9(2):109-10. PMC: 2854288. DOI: 10.4161/cbt.9.2.10583. View