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 mediating AMPA receptor trafficking and actin cytoskeletal dynamics in dendritic spines. In addition, Arc protein forms capsid-like particles, which can encapsulate and transfer mRNA in extracellular vesicles (EVs) between neurons, that could be a possible mechanism to control 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 glioma tumor tissue and in several human glioma cell lines. Our results show that glioma cells can produce EVs containing Arc protein and Arc mRNA (or Arc EVs). It was found that pure 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. Overexpression of Arc in glioma cell lines significantly increases EV production, alters EV morphology, and significantly enhances intercellular transfer of highly expressed mRNA in glioma cell culture. These findings indicate involvement of Arc EVs into intercellular mRNA transfer between glioma cells that could contribute to tumor progression and affect synaptic plasticity in cancer patients.