RAPAMYCIN-INDUCED RESCUE OF AUTOPHAGY DRIVES GLIOBLASTOMA STEM/PROGENITOR CELLS DIFFERENTIATION

Glioblastoma (GBM; WHO grade IV glioma) is the most common, aggressive and malignant primary brain tumor. Recently, evidence indicates that GBM proliferation and tissue invasion are supported by the presence of cancer stem/progenitor cells niches, named GSPCs (Glioblastoma Stem/Progenitor Cells). In these niches, cells share the biological properties of normal stem cells, such as self-renewal, pluripotency and marked proliferation; they are key in tumor initiation, relapse and resistance to standard treatments. At molecular level, GSPCs are characterized by marked up-regulation of the mammalian Target Of Rapamycin (mTOR), a master regulator of cell growth and metabolism. In particular, mTOR acts as a negative modulator of autophagy. Although autophagy suppression in GBM is well established, its significance remains controversial, whereas the increase in autophagy may lead either to cell differentiation or to cell death, depending on the experimental conditions and the dose of autophagy inducers. Therefore in the present study we analyzed the efficacy of the mTOR inhibitor and autophagy activator, rapamycin, on GBM cell proliferation and cell differentiation. We found that rapamycin induced a marked reduction of the stemness marker Nestin, along with an increase for the early and late neuronal marker, beta-III tubulin and NeuN, respectively. No effects were noticed for the glial marker GFAP. These effects, together with evidence of a massive tumor volume reduction in the absence of any cell death, generate the working hypothesis that rapamycin acts on GBM both reducing cell proliferation and promoting GSPCs phenotypic switch towards neurons.