Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner

Thomas J Turbyville; Demirkan B Gürsel; Robert G Tuskan; Jessica C Walrath; Claudia A Lipschultz; Stephen J Lockett; David F Wiemer; John A Beutler; Karlyne M Reilly

doi:10.1158/1535-7163.MCT-09-0834

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Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner

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Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner

Thomas J Turbyville, Demirkan B Gürsel, Robert G Tuskan, Jessica C Walrath, Claudia A Lipschultz, Stephen J Lockett, David F Wiemer, John A Beutler and Karlyne M Reilly

Molecular cancer therapeutics, Vol.9(5), pp.1234-1243

05/2010

DOI: 10.1158/1535-7163.MCT-09-0834

PMCID: PMC3268685

PMID: 20442305

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Abstract

Neurofibromatosis type 1 (NF1) is the most common genetic disease affecting the nervous system. Patients typically develop many tumors over their lifetime, leading to increased morbidity and mortality. The NF1 gene, mutated in NF1, is also commonly mutated in sporadic glioblastoma multiforme (GBM). Because both NF1 and GBM are currently incurable, new therapeutic approaches are clearly needed. Natural products represent an opportunity to develop new therapies, as they have been evolutionarily selected to play targeted roles in organisms. Schweinfurthin A is a prenylated stilbene natural product that has previously shown specific inhibitory activity against brain and hematopoietic tumor lines. We show that patient-derived GBM and NF1 malignant peripheral nerve sheath tumor (MPNST) lines, as well as tumor lines derived from the Nf1-/+;Trp53-/+ (NPcis) mouse model of astrocytoma and MPNST are highly sensitive to inhibition by schweinfurthin A and its synthetic analogs. In contrast, primary mouse astrocytes are resistant to the growth inhibitory effects of schweinfurthin A, suggesting that schweinfurthin A may act specifically on tumor cells. Stable transfection of the GTPase-activating protein related domain of Nf1 into Nf1-/-;Trp53-/- astrocytoma cells confers resistance to schweinfurthin A. In addition, the profound effect of schweinfurthin A on dynamic reorganization of the actin cytoskeleton led us to discover that schweinfurthin A inhibits growth factor-stimulated Rho signaling. In summary, we have identified a class of small molecules that specifically inhibit growth of cells from both central and peripheral nervous system tumors and seem to act on NF1-deficient cells through cytoskeletal reorganization correlating to changes in Rho signaling.

Humans

Brain Neoplasms - pathology

Stilbenes - pharmacology

Brain Neoplasms - metabolism

Glioma - metabolism

Glioma - genetics

Glioma - pathology

Neurofibromatosis 1 - metabolism

Genes, Neurofibromatosis 1 - physiology

Neurofibromin 1 - chemistry

Drug Evaluation, Preclinical

Neurofibromin 1 - metabolism

Animals, Newborn

Neurofibromin 1 - physiology

Cells, Cultured

Brain Neoplasms - genetics

Mice, Transgenic

Protein Structure, Tertiary - genetics

rho GTP-Binding Proteins - physiology

Neurofibromatosis 1 - pathology

Animals

Substrate Specificity - drug effects

Signal Transduction - drug effects

Models, Biological

rho GTP-Binding Proteins - metabolism

Cell Proliferation - drug effects

Mice

Protein Structure, Tertiary - physiology

Details

Title: Subtitle: Schweinfurthin A selectively inhibits proliferation and Rho signaling in glioma and neurofibromatosis type 1 tumor cells in a NF1-GRD-dependent manner
Creators: Thomas J Turbyville - National Cancer Institute-Frederick, Frederick, Maryland, USA
Demirkan B Gürsel
Robert G Tuskan
Jessica C Walrath
Claudia A Lipschultz
Stephen J Lockett
David F Wiemer
John A Beutler
Karlyne M Reilly
Resource Type: Journal article
Publication Details: Molecular cancer therapeutics, Vol.9(5), pp.1234-1243
Publisher: United States
DOI: 10.1158/1535-7163.MCT-09-0834
PMID: 20442305
PMCID: PMC3268685
ISSN: 1535-7163
eISSN: 1538-8514
Grant note: HHSN261200800001E / PHS HHS Z01 BC010541-06 / Intramural NIH HHS HHSN261200800001C / CCR NIH HHS HHSN261200800001E / NCI NIH HHS
Language: English
Date published: 05/2010
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9983985875802771

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31 Times Cited - Web of Science

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