Involvement of mTORC1 and mTORC2 in regulation of glioblastoma multiforme growth and motility.
The AKT/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in glioblastoma multiforme (GBM) oncogenesis due to activation of AKT. We studied two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), through which mTOR controls cell survival, growth and motility. Inhibition of mTOR by rapamycin (RAPA) resulted in time-dependent suppression of S6 ribosomal protein (pS6KSer235/236; mTORC1 substrate) and caused transient suppression of pAKTSer473 (mTORC2 substrate) at 1 to 3 h followed by a consistent increase from 6 to 24 h. Inhibition of mTOR or phosphoinositide 3-kinase (PI3K) suppressed platelet-derived growth factor (PDGF)- or fibronectin (FN)-induced activation of p70S6KThr389. Combined inhibition of mTOR and PI3K abolished PDGF- or FN-induced activation of STAT3Ser727. Expression of pAKT was suppressed by siRNA silencing of mTORC2 co-protein rictor, but not by mTORC1 co-protein raptor. GBM cell proliferation and motility paralleled the activation of mTORC2. Combined inhibition of mTOR and PI3K had an additive effect on suppressing cell growth and motility. PDGF-induced nuclear localization of mTOR was blocked by pre-treatment with RAPA. The results demonstrated that an activation of mTORC2 occurs when mTORC1 is inhibited by RAPA. Therefore, simultaneous suppression of mTORC1 and mTORC2 may provide novel therapy for GBM.
Gulati
Nicholas
N
Department of Neurosurgery, New York Medical College, Valhalla, NY 10595, USA.
Karsy
Michael
M
Albert
Ladislau
L
Murali
Raj
R
Jhanwar-Uniyal
Meena
M
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D046912:Multiprotein Complexes; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013912:Threonine; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D002867:Chromones; D005353:Fibronectins; D009025:Morpholines; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D050796:STAT3 Transcription Factor; D012694:Serine; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D013912:Threonine; C492571:RICTOR protein, human; C463659:RPTOR protein, human; C494086:STAT3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human