Raloxifene prevents stress granule dissolution, impairs translational control and promotes cell death during hypoxia in glioblastoma cells.

Cell Death & Disease
Kathleen M AttwoodAdrienne Weeks

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor, and it has a uniformly poor prognosis. Hypoxia is a feature of the GBM microenvironment, and previous work has shown that cancer cells residing in hypoxic regions resist treatment. Hypoxia can trigger the formation of stress granules (SGs), sites of mRNA triage that promote cell survival. A screen of 1120 FDA-approved drugs identified 129 candidates that delayed the dissolution of hypoxia-induced SGs following a return to normoxia. Amongst these candidates, the selective estrogen receptor modulator (SERM) raloxifene delayed SG dissolution in a dose-dependent manner. SG dissolution typically occurs by 15 min post-hypoxia, however pre-treatment of immortalized U251 and U3024 primary GBM cells with raloxifene prevented SG dissolution for up to 2 h. During this raloxifene-induced delay in SG dissolution, translational silencing was sustained, eIF2α remained phosphorylated and mTOR remained inactive. Despite its well-described role as a SERM, raloxifene-mediated delay in SG dissolution was unaffected by co-administration of β-estradiol, nor did β-estradiol alone have any effect on SGs. Importantly, the combination of raloxifene and hypoxia resulted in increased num...Continue Reading

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Citations

Jun 8, 2021·Frontiers in Cell and Developmental Biology·Danae Campos-MeloMichael J Strong
Jun 20, 2021·Trends in Cancer·Margot LavaléeDon-Marc Franchini
Aug 31, 2021·International Journal of Cancer. Journal International Du Cancer·Debmita Chatterjee, Oishee Chakrabarti

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Methods Mentioned

BETA
nucleotide exchange
environmental stress
fluorescence imager
Protein Assay
RNA-Seq
flow cytometry
acetylation

Key Resources (RRID) Mentioned

CVCL_IR67

Software Mentioned

Arrayscan
ArrayScan V TI HCS
RStudio
R
GlioVis
CellProfiler
Excel
ImageLab

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