Retrovirus-Like Gag Protein Arc/Arg3.1 is Involved in Extracellular-Vesicle-Mediated mRNA Transfer between Glioma Cells

Abstract

Activity-regulated cytoskeleton-associated (Arc) protein is expressed in neural tissue of vertebrates, where it plays a pivotal role in modulation of synaptic communication. In addition, Arc protein forms capsid-like particles, which can encapsulate and transfer mRNA in extracellular vesicles (EVs) between neurons, that could modulate synaptic function and plasticity. Glioma cell networks actively interact with neurons via paracrine signaling and formation of neurogliomal glutamatergic synapses that contribute to cancer cell survival, proliferation, and invasion. Here, we revealed that Arc is expressed in human glioma cell lines, which can produce EVs containing Arc protein and Arc mRNA (or "Arc EVs"). Recombinant Arc protein binds to Arc mRNA with 1.5-fold higher affinity as compared with control mCherry mRNA. Arc EVs from U87 glioma cells internalize and deliver Arc mRNA to recipient U87 cells, where it is translated into a protein. Arc overexpression significantly increases EV production, alters EV morphology, and enhances intercellular transfer of highly expressed mRNA in glioma cell culture. These findings indicate involvement of Arc EVs into mRNA transfer between glioma cells that could contribute to tumor progression and affect synaptic plasticity in cancer patients.