title: 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.
authors.affiliation: National Centre for Cell Science (NCCS), Savitribai Phule Pune University Campus, Pune, India.
authors.forename: Goparaju
authors.initials: G
authors.lastname: Chandrika
authors.affiliation: National Centre for Cell Science (NCCS), Savitribai Phule Pune University Campus, Pune, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Natesh
authors.affiliation: Department of Neurosurgery, D.Y. Patil Medical College, Pune, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Ranade
authors.affiliation: Department of Neurosurgery, Cimet's Inamdar Multispecialty Hospital, Pune, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Chugh
authors.affiliation: National Centre for Cell Science (NCCS), Savitribai Phule Pune University Campus, Pune, India.
authors.forename: Padma
authors.initials: P
authors.lastname: Shastry
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009287:Naphthyridines / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D010648:Phenylacetates / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D059016:Tumor Microenvironment / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D000970:Antineoplastic Agents; D007211:Indoles; D016328:NF-kappa B; D009287:Naphthyridines; D010648:Phenylacetates; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C105354:temiverine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051571:Protein Kinase C-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C572919:PP242; D020123:Sirolimus