Abstract 3429: Coordination of cell cycle repression and reduced cytoskeletal tension by the small molecule natural product, Schweinfurthin A.

Abstract

Abstract Malignant Peripheral Nerve Sheath Tumors (MPNST) are a frequent cause of morbidity and mortality in Neurofibromatosis type 1 patients, and arise in part from loss of the tumor suppressor function of the NF1 gene product, neurofibromin. We have previously shown that MPNST tumor cell lines, as well as astrocytoma cell lines, derived from both patients and a Nf1-/+;Trp53-/+ (NPcis) mouse model are differentially sensitive to the natural product, Schweinfurthin A (SA). In addition to its anti-proliferative effects, SA caused dramatic reorganization of the actin cytoskeleton. When the NF1 Ras-regulatory domain was re-expressed in an Nf1-/- astrocytoma cell line derived from the NPcis model, these cells became resistant to the effects of SA. This led us to hypothesize that SA mediates its effects on the actin cytoskeleton and proliferation by phenocopying neurofibromin in its regulation of Rho and mitogenic signaling pathways. Our objective is to understand if and how this is the case. To further that end, the goal of this study was to begin to probe the coordination of proliferation and cytoskeletal tension, as has been previously reported in other studies. We cultured individual SA- and DMSO-treated MPNST cells derived from the NPcis model onto pre-defined micropatterns of fibronectin. By constraining cell shape, quantitative structural properties of cells were revealed that were otherwise masked when cells were grown on standard coverslips. We observed dose-dependent increases in the concave curvature of cell edge segments not attached to the underlying fibronectin. Such curvature is known to represent decreased cell tension exerted by the actin cytoskeleton. Across the same SA doses, we measured a decrease in cyclin D1 and cyclin D3 total protein levels and a decrease in retinoblastoma protein phosphorylation, which was consistent with flow cytometry data showing a G1 blockade. Thus, we conclude that proliferation and cytoskeletal tension are coordinated in cells sensitive to the candidate drug, SA. Funded by NCI Contract No. HHSN261200800001E. Citation Format: Thomas Turbyville, Alla Brafman, De Chen, Kathryn Romanchuck, John Beutler, Karlyne Reilly, Stephen Lockett. Coordination of cell cycle repression and reduced cytoskeletal tension by the small molecule natural product, Schweinfurthin A. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3429. doi:10.1158/1538-7445.AM2013-3429