Inhibition of mTOR Activates the MAPK Pathway in Glioblastoma Multiforme.
Tumorigenesis of glioblastoma multiforme (GBM), the most aggressive primary intracranial neoplasm, is associated with aberrant PI3K/AKT/mTOR signaling. Inhibitors of mTOR, such as rapamycin (RAPA) or its analogs, have provided limited benefit. Here, we aim to decipher the signaling pathways involved in RAPA resistance. We found that RAPA induced a time-dependent activation of MAPK (pERK1/2) and MEK1/2. Inhibition of upstream kinase MEK1/2 by U0126 partially suppressed RAPA-induced ERK1/2 activation. Small interfering RNA suppression of mTOR resulted in higher pERK1/2 levels and pre-treatment with RAPA potentiated PDGF-induced activation of ERK1/2. Furthermore, nuclear localization of pERK1/2 was evident following RAPA, which was MEK1/2-dependent. Cell proliferation was significantly suppressed by combined MEK1/2 and mTOR inhibition compared to mTOR inhibition alone. These results demonstrate activation of a mitogenic pathway involving a feedback mechanism between mTOR and PI3K/ERK1/2 and support the basis for combined inhibitors in GBM treatment.
Albert
Ladislau
L
Departments of Neurosurgery & Experimental Pathology, New York Medical College, Valhalla, NY 10595, U.S.A.
Karsy
Michael
M
Murali
Raj
R
Jhanwar-Uniyal
Meena
M
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005246:Feedback; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus