Ral overactivation in malignant peripheral nerve sheath tumors

Vidya Bodempudi, Farnaz Yamoutpoor, Weihong Pan, Arkadiusz Z Dudek, Tuba Esfandyari, Mark Piedra, Dusica Babovick-Vuksanovic, Richard A. Woo, Victor F. Mautner, Lan Kluwe, D. Wade Clapp, George H. DeVries, Stacey L. Thomas, Andreas Kurtz, Luis F. Parada, Faris Farassati

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Ras leads an important signaling pathway that is deregulated in neurofibromatosis type 1 and malignant peripheral nerve sheath tumor (MPNST). In this study, we show that overactivation of Ras and many of its downstream effectors occurred in only a fraction of MPNST cell lines. RalA, however, was overactivated in all MPNST cells and tumor samples compared to nontransformed Schwann cells. Silencing Ral or inhibiting it with a dominant-negative Ral (Ral S28N) caused a significant reduction in proliferation, invasiveness, and in vivo tumorigenicity of MPNST cells. Silencing Ral also reduced the expression of epithelial mesenchymal transition markers. Expression of the NF1-GTPase-related domain (NF1-GRD) diminished the levels of Ral activation, implicating a role for neurofibromin in regulating RalA activation. NF1-GRD treatment caused a significant decrease in proliferation, invasiveness, and cell cycle progression, but cell death increased. We propose Ral overactivation as a novel cell signaling abnormality in MPNST that leads to important biological outcomes with translational ramifications.

Original languageEnglish (US)
Pages (from-to)3964-3974
Number of pages11
JournalMolecular and cellular biology
Volume29
Issue number14
DOIs
StatePublished - Jul 2009

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