The emerging role of mTOR up-regulation in brain astrocytoma

Larisa Ryskalin¹, Fiona Limanaqi¹, Francesca Biagioni², Alessandro Frati², Vincenzo Esposito², Maria Teresa Calierno², Paola Lenzi¹ and Francesco Fornai<sup>1,2

1</sup>Department of Translational Research and New Technologies in Medicine and Surgery, Human Anatomy, Pisa University of Pisa and ²I.R.C.C.S. Neuromed, Pozzilli, Isernia, Italy

Offprint requests to: Francesco Fornai, Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55 – 56126 Pisa, Italy. e-mail: francesco.fornai@med.unipi.it

Summary. The present manuscript is an overview of various effects of mTOR up-regulation in astrocytoma with an emphasis on its deleterious effects on the proliferation of Glioblastoma Multiforme. The manuscript reports consistent evidence indicating the occurrence of mTOR up-regulation both in experimental and human astrocytoma. The grading of human astrocytoma is discussed in relationship with mTOR up-regulation. In the second part of the manuscript, the biochemical pathways under the influence of mTOR are translated to cell phenotypes which are generated by mTOR up-regulation and reverted by its inhibition. A special section is dedicated to the prominent role of autophagy in mediating the effects of mTOR in glioblastoma. In detail, autophagy inhibition produced by mTOR up-regulation determines the fate of cancer stem cells. On the other hand, biochemical findings disclose the remarkable effects of autophagy activators as powerful inducers of cell differentiation with a strong prevalence towards neuronal phenotypes. Thus, mTOR modulation acts on the neurobiology of glioblastoma just like it operates in vivo at the level of brain stem cell niches by altering autophagy-dependent cell differentiation. In the light of such a critical role of autophagy we analyzed the ubiquitin proteasome system. The merging between autophagy and proteasome generates a novel organelle, named autophago-proteasome which is strongly induced by mTOR inhibitors in glioblastoma cells. Remarkably, when mTOR is maximally inhibited the proteasome component selectively moves within autophagy vacuoles, thus making the proteasome activity dependent on the entry within autophagy compartment. Histol Histopathol 32, 413-431 (2017)

Key words: Autophagy, Autophagoproteasome, Cancer stem cells, Glioblastoma, Stem cell differentiation

DOI: 10.14670/HH-11-835