Eukaryotic initiation factor 5B (eIF5B) provides a critical cell survival switch to glioblastoma cells via regulation of apoptosis

Joseph A Ross; Keiran Vanden Dungen; Kamiko R Bressler; Mikayla Fredriksen; Divya Khandige Sharma; Nirujah Balasingam; Nehal Thakor

doi:10.1038/s41419-018-1283-5

Eukaryotic initiation factor 5B (eIF5B) provides a critical cell survival switch to glioblastoma cells via regulation of apoptosis

Cell Death Dis. 2019 Jan 22;10(2):57. doi: 10.1038/s41419-018-1283-5.

Authors

Joseph A Ross¹, Keiran Vanden Dungen¹, Kamiko R Bressler¹, Mikayla Fredriksen¹, Divya Khandige Sharma¹, Nirujah Balasingam¹, Nehal Thakor^{2

3

4}

Affiliations

¹ Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, AB, T1K 3M4, Canada.
² Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive W, Lethbridge, AB, T1K 3M4, Canada. nthakor@uleth.ca.
³ Canadian Centre for Behavioral Neuroscience (CCBN), Department of Neuroscience, University of Lethbridge, 4401 University Drive W, Lethbridge, AB, T1K 3M4, Canada. nthakor@uleth.ca.
⁴ Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada. nthakor@uleth.ca.

Abstract

Physiological stress conditions attenuate global mRNA translation via modifications of key eukaryotic initiation factors. However, non-canonical translation initiation mechanisms allow cap-independent translation of certain mRNAs. We have previously demonstrated that eIF5B promotes cap-independent translation of the mRNA encoding the antiapoptotic factor, XIAP, during cellular stress. Here, we show that depletion of eIF5B sensitizes glioblastoma multiforme cells to TRAIL-induced apoptosis by a pathway involving caspases-8, -9, and -7, with no significant effect on cell cycle progression. eIF5B promotes evasion of apoptosis by promoting the translation of several IRES-containing mRNAs, encoding the antiapoptotic proteins XIAP, Bcl-xL, cIAP1, and c-FLIP_S. We also show that eIF5B promotes translation of nuclear factor erythroid 2-related factor 2 and suggest that reactive oxygen species contribute to increased apoptosis under conditions of eIF5B depletion. Finally, eIF5B depletion leads to decreased activation of the canonical NF-κB pathway. Taken together, our data suggest that eIF5B represents a regulatory node, allowing cancer cells to evade apoptosis by promoting the translation of pro-survival proteins from IRES-containing mRNAs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Apoptosis / physiology
Cell Line, Tumor
Cell Survival / physiology
Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Drug Resistance, Neoplasm
Eukaryotic Initiation Factors / deficiency
Eukaryotic Initiation Factors / genetics*
Eukaryotic Initiation Factors / metabolism
Glioblastoma / drug therapy
Glioblastoma / genetics*
Glioblastoma / metabolism
Glioblastoma / pathology*
HEK293 Cells
Humans
Inhibitor of Apoptosis Proteins / biosynthesis
Inhibitor of Apoptosis Proteins / genetics
NF-E2-Related Factor 2 / biosynthesis
NF-E2-Related Factor 2 / genetics
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Small Interfering / genetics
Recombinant Proteins / pharmacology
TNF-Related Apoptosis-Inducing Ligand / pharmacology
Transfection
Up-Regulation
X-Linked Inhibitor of Apoptosis Protein / biosynthesis
X-Linked Inhibitor of Apoptosis Protein / genetics
bcl-X Protein / biosynthesis
bcl-X Protein / genetics

Substances

BCL2L1 protein, human
CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
Eukaryotic Initiation Factors
Inhibitor of Apoptosis Proteins
NF-E2-Related Factor 2
NFE2L2 protein, human
RNA, Messenger
RNA, Small Interfering
Recombinant Proteins
TNF-Related Apoptosis-Inducing Ligand
TNFSF10 protein, human
X-Linked Inhibitor of Apoptosis Protein
XIAP protein, human
bcl-X Protein
eukaryotic initiation factor-5B