RT Journal Article
SR Electronic
T1 Inhibition of mTOR Activates the MAPK Pathway in Glioblastoma Multiforme
JF Cancer Genomics - Proteomics
JO Cancer Genomics Proteomics
FD International Institute of Anticancer Research
SP 255
OP 261
VO 6
IS 5
A1 LADISLAU ALBERT
A1 MICHAEL KARSY
A1 RAJ MURALI
A1 MEENA JHANWAR-UNIYAL
YR 2009
UL http://cgp.iiarjournals.org/content/6/5/255.abstract
AB 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.