Modulation of stress granules by lobeline increases cell death in hypoxia and impacts the ability of glioblastoma cells to secrete extracellular vesicles.

Abstract

Glioblastoma (GBM) is a devastating universally fatal primary brain cancer. Novel therapeutic strategies are required to alter disease course and improve survival in these patients. There is increasing evidence that modulating cancer's ability to respond to and survive cellular stress through RNA stress granules (SGs) may be a novel approach to cancer therapeutics. SGs are cytoplasmic aggregates of untranslated mRNAs and RNA binding proteins formed in response to a variety of cellular stressors, that allow cells to temporarily prioritize translation of stress-related proteins. A previous drug screen identified the dopamine modulator lobeline as a factor affecting SG disassembly in GBM cells. Lobeline impairs GBM cell survival by impairing SG disassembly after hypoxia. Specifically, after a hypoxic challenge, lobeline "locks" cells in a stressed state, even after re-exposure to normoxia. This is characterized by retained SGs, elevated levels of phosphorylated eIF2α and a sustained reduction in global protein translation. The disruption of the canonical stress response induced by lobeline ultimately results in increased cell death in both primary and immortalized GBM cell lines. Interestingly, lobeline also reduces post-hypoxia extracellular vesicle (EV) release, potentially through sequestration of the SG and EV protein, YBX1. Taken together, this adds to the literature that modulating stress and SG dynamics may be useful alone or to potentiate other treatment modalities affecting stress in GBM.