RNA derived from cancer cells as a scaffold for amyloid-β25-35 aggregation: the effect of RNA methylation and rRNA...

Besides a well-established protein aggregation-mediated pathologies in neurodegenerative diseases, protein misfolding and subsequent accumulation of non-functional aggregates may also have a role during cancer progression promoting cancer cell survival and affecting drug responses. A number of factors may modulate the process of protein aggregation. However, the role of RNA as a scaffold and its methylation status were not elucidated yet. In the present study, we have used a cellular model of cancer, namely osteosarcoma (OS) cells to investigate RNA-mediated amyloid-β (Aβ) aggregation in the biological system not related to Aβ-mediated pathology. In the presence of Aβ25-35, RNA isolated from OS cells promoted the formation of protein aggregates in a concentration-dependent manner in vitro. Drug-induced senescent OS cells devoid of two m⁵C RNA methyltransferases TRDMT1 and NSUN2 had limited ability to form protein aggregates. Nevertheless, this observation was associated with rRNA status and the expression of rRNA-related genes rather than RNA methylation. In contrast, RNA secreted by senescent wild type (WT) OS cells was characterized by increased m⁵C levels compared to RNA intracellular pools that was accompanied by its ability to stimulate the formation of Aβ25-35 aggregates. In conclusion, we show for the first time that RNA derived from cancer cells may be a scaffold promoting the formation of Aβ25-35 aggregates. More studies are needed to validate the RNA-mediated protein aggregation in cellular systems and its modulation by RNA methylation and rRNA status. RNA amyloidogenic activity should also be assessed in the presence of full-length Aβ.