Proteomic analysis reveals hyperactivation of the mammalian target of rapamycin pathway in neurofibromatosis 1-associated human and mouse brain tumors.
Individuals with the tumor predisposition syndrome, neurofibromatosis 1 (NF1), are prone to development of nervous system tumors, including neurofibromas and pilocytic astrocytomas. Based on the ability of the NF1 gene product (neurofibromin) to function as a GTPase activating protein for RAS, initial biologically based therapies for NF1-associated tumors focused on the use of RAS inhibitors, but with limited clinical success. In an effort to identify additional targets for therapeutic drug design in NF1, we used an unbiased proteomic approach to uncover unanticipated intracellular signaling pathways dysregulated in Nf1-deficient astrocytes. We found that the expression of proteins involved in promoting ribosome biogenesis was increased in the absence of neurofibromin. In addition, Nf1-deficient astrocytes exhibit high levels of mammalian target of rapamycin (mTOR) pathway activation, which was inhibited by blocking K-RAS or phosphatidylinositol 3-kinase activation. This mTOR pathway hyperactivation was reflected by high levels of ribosomal S6 activation in both Nf1 mutant mouse optic nerve gliomas and in human NF1-associated pilocytic astrocytoma tumors. Moreover, inhibition of mTOR signaling in Nf1-/- astrocytes abrogated their growth advantage in culture, restoring normal proliferative rates. These results suggest that mTOR pathway inhibition may represent a logical and tractable biologically based therapy for brain tumors in NF1.
Dasgupta
Biplab
B
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Yi
Yijun
Y
Chen
David Y
DY
Weber
Jason D
JD
Gutmann
David H
DH
D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D012333:RNA, Messenger; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse