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[Cancer Research 65, 2755-2760, April 1, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

Proteomic Analysis Reveals Hyperactivation of the Mammalian Target of Rapamycin Pathway in Neurofibromatosis 1–Associated Human and Mouse Brain Tumors

Biplab Dasgupta1, Yijun Yi1, David Y. Chen2, Jason D. Weber2 and David H. Gutmann1

Departments of 1 Neurology and 2 Internal Medicine, Washington University School of Medicine, St. Louis, Missouri

Requests for reprints: David H. Gutmann, Department of Neurology, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-362-7379; Fax: 314-362-2388; E-mail: pouchera{at}neuro.wustl.edu.

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.

Key Words: neurofibromatosis 1 • RAS • mTOR • astrocytoma • glioma




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Copyright © 2005 by the American Association for Cancer Research.