Abstract
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-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1β 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 TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB 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.
Highlights
We found that mTOR inhibitors effectively reduced the transcript and protein level of membrane potential (MMP)-9 and MMP-2
Our results revealed that MMP-9 activity reduced by mTOR inhibitors was independent of TIMP1
To decipher the mechanism involved in inhibiting the invasiveness and modulating the MMP activity, we examined the impact of the mTOR inhibitors on NFκ B and protein kinase C (PKC)-α -mediated signaling
Summary
The mTOR pathway is highly activated in GBMs and one of the most studied inhibitors of mTOR is Rapamycin (RAP), an FDA approved drug that works through a gain-of-function allosteric mechanism. RAP binds to the intracellular protein FKBP12 to generate a drug-receptor complex that binds to and inhibits the kinase activity of mTORC113. The general anticancer activity shown by original mTOR allosteric inhibitors, RAP and its analogs (rapalogs) in most cancers, has supported the development of novel mTOR kinase inhibitors (TORKinibs) that inhibit mTORC1 and mTORC2 more effectively[18]. We investigated the anti-invasive and -migration potential of mTOR inhibitors (RAP, TEM, TOR and PP242) in human GBM cells. We show that the mTOR inhibitors suppressed invasion and migration in GBM cells in the presence of TNFα and tumor promoter PMA mediated by reduction of PKC-α activity and downregulation of NFκ B
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