Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling

Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period < 1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin- 1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-alpha (TNF alpha) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNF alpha and IL1 beta suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNF alpha and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-alpha) activity and downregulation of NF kappa B. TNF alpha- induced transcripts of NF kappa B targets - VEGF, pentraxin- 3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.