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

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.

Regulation of glioma cell invasion by 3q26 gene products PIK3CA, SOX2 and OPA1

“…Maintaining SOX2 activation by PI3K/AKT pathway activity provided a first molecular link between the 3q26 gene products PIK3CA and SOX2. Of note, mTOR, a downstream target of PI3K/AKT signaling, was previously identified as a regulator of glioma cell invasion and proposed as target for controlling cell invasion (6). However, we found that PI3K/AKT directly regulates SOX2 activity in ways that do not (evidently) involve mTORC1.…”

Rapamycin promotes differentiation increasing βIII-tubulin, NeuN, and NeuroD while suppressing nestin expression in glioblastoma cells

“…In fact, when considering all the properties of stem-like GBM-initiating cells such as cell proliferation, expression of stemness antigens as well as loss of cell aggregation and increased cell migration, all of them are affected by mTOR inhibition [5, 6, 9, 16, 23, 24]. …”

Mammalian target of rapamycin inhibitors, temsirolimus and torin 1, attenuate stemness-associated properties and expression of mesenchymal markers promoted by phorbol-myristate-acetate and oncostatin-M in glioblastoma cells

“…46 We have previously demonstrated that mTOR inhibitors, RAP, TEM, TOR, and PP242, reduced PKC activity in GBM cells. 26 In this context, we show here that TEM and TOR markedly reduced the Figure 7. mTOR inhibitors reverse the neurosphere formation promoted by PMA and OSM.…”

“…We recently reported that mTOR inhibitors-rapamycin (RAP), TEM, TOR, and PP242-suppressed invasion and migration induced by tumor necrosis factor-alpha (TNFα) and tumor promoter (phorbol-myristate-acetate (PMA)) in human GBM cells. 26 Given that invasion and migration are characteristics associated with mesenchymal phenotype and stemness-like features in GBM, the aim of this study was to investigate the potential of mTOR inhibitors in affecting the mesenchymal markers and stemness. We demonstrate that TEM and TOR inhibit mesenchymal markers and stem cell-like traits induced by PMA and oncostatin-M (OSM).…”