title: 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.
abstract: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway is crucial for tumor survival, proliferation, and progression, making it an attractive target for therapeutic intervention. In glioblastoma, activated mammalian target of rapamycin promotes invasive phenotype and correlates with poor patient survival. A wide range of mammalian target of rapamycin inhibitors are currently being evaluated for cytotoxicity and anti-proliferative activity in various tumor types but are not explored sufficiently for controlling tumor invasion and recurrence. We recently reported that mammalian target of rapamycin inhibitors-rapamycin, temsirolimus, torin 1, and PP242-suppressed invasion and migration promoted by tumor necrosis factor-alpha and phorbol-myristate-acetate in glioblastoma cells. As aggressive invasion and migration of tumors are associated with mesenchymal and stem-like cell properties, this study aimed to examine the effect of mammalian target of rapamycin inhibitors on these features in glioblastoma cells. We demonstrate that temsirolimus and torin 1 effectively reduced the constitutive as well as phorbol-myristate-acetate/oncostatin-M-induced expression of mesenchymal markers (fibronectin, vimentin, and YKL40) and neural stem cell markers (Sox2, Oct4, nestin, and mushashi1). The inhibitors significantly abrogated the neurosphere-forming capacity induced by phorbol-myristate-acetate and oncostatin-M. Furthermore, we demonstrate that the drugs dephosphorylated signal transducer and activator transcription factor 3, a major regulator of mesenchymal and neural stem cell markers implicating the role of signal transducer and activator transcription factor 3 in the inhibitory action of these drugs. The findings demonstrate the potential of mammalian target of rapamycin inhibitors as "stemness-inhibiting drugs" and a promising therapeutic approach to target glioma stem cells.
authors.affiliation: 1 National Centre for Cell Science (NCCS), Savitribai Phule Pune University, Pune, India.
authors.forename: Goparaju
authors.initials: G
authors.lastname: Chandrika
authors.affiliation: 1 National Centre for Cell Science (NCCS), Savitribai Phule Pune University, Pune, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Natesh
authors.affiliation: 2 Department of Neurosurgery, D. Y. Patil Medical College, Hospital & Research Centre, Pune, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Ranade
authors.affiliation: 3 Department of Neurosurgery, CIMET's Inamdar Multispecialty Hospital, Pune, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Chugh
authors.affiliation: 1 National Centre for Cell Science (NCCS), Savitribai Phule Pune University, Pune, India.
authors.forename: Padma
authors.initials: P
authors.lastname: Shastry
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005353:Fibronectins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D009287:Naphthyridines / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects; D053683:Oncostatin M / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000031:analogs & derivatives; D014746:Vimentin / Q000096:biosynthesis
chemical_list: D005353:Fibronectins; D009287:Naphthyridines; D053683:Oncostatin M; D019869:Phosphatidylinositol 3-Kinases; D050796:STAT3 Transcription Factor; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D013755:Tetradecanoylphorbol Acetate; D014746:Vimentin; C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C508351:OSM protein, human; C494086:STAT3 protein, human; C016658:phorbolol myristate acetate; C401859:temsirolimus; C546842:MTOR protein, human
keywords: Glioblastoma; mammalian target of rapamycin inhibitors; mesenchymal markers; signal transducer and activator transcription factor 3; stemness