Autophagy Activation Associates with Suppression of Prion Protein and Improved Mitochondrial Status in Glioblastoma Cells

Cells from glioblastoma multiforme (GBM) feature up-regulation of the mechanistic Tar-23 get of Rapamycin (mTOR), which brings deleterious effects on malignancy and disease course. At 24 cellular level, up-regulation of mTOR affects a number of downstream pathways and suppresses 25 autophagy, which is relevant for the neurobiology of GBM. In fact, autophagy acts on several targets 26 such as protein clearance and mitochondrial status, which are key in promoting the malignancy 27 GBM. A defective protein clearance extends to cellular Prion Protein (PrPc). Recent evidence indi-28 cates that PrPc promotes stemness and alters mitochondrial turnover. Therefore, the present study 29 measures whether in GBM cells abnormal amount of PrPc and mitochondrial alterations are con-30 comitant in baseline conditions and whether they are reverted by mTOR inhibition. Protein related 31 to mitochondrial turnover were concomitantly assessed. High amount of PrPc and altered mito-32 chondria were both mitigated dose-dependently by the mTOR inhibitor rapamycin, which pro-33 duced a persistent activation of the autophagy flux and shifted proliferating cells from S to G1 cell 34 cycle phase. Similarly, mTOR suppression produces a long-lasting increase of proteins promoting 35 mitochondrial turnover including Pink1/Parkin. These findings provide novel evidence about the 36 role of autophagy in the neurobiology of GBM