This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Finlay, G. A. Articles by Toksoz, D. Search for Related Content PubMed PubMed Citation Articles by Finlay, G. A. Articles by Toksoz, D.

Selective Inhibition of Growth of Tuberous Sclerosis Complex 2–Null Cells by Atorvastatin Is Associated with Impaired Rheb and Rho GTPase Function and Reduced mTOR/S6 Kinase Activity

¹ Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, Tufts-New England Medical Center; ² Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Requests for reprints: Geraldine A. Finlay or Deniz Toksoz, Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, TNEMC #257, 750 Washington Street, Boston, MA 02111. Phone: 617-636-1041; E-mail: gfinlay{at}tufts-nemc.org or dtoksoz{at}tufts-nemc.org.

Inactivating mutations in the tuberous sclerosis complex 2 (TSC2) gene, which encodes tuberin, result in the development of TSC and lymphangioleiomyomatosis (LAM). The tumor suppressor effect of tuberin lies in its GTPase-activating protein activity toward Ras homologue enriched in brain (Rheb), a Ras GTPase superfamily member. The statins, 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, have pleiotropic effects which may involve interference with the isoprenylation of Ras and Rho GTPases. We show that atorvastatin selectively inhibits the proliferation of Tsc2^–/– mouse embryo fibroblasts and ELT-3 smooth muscle cells in response to serum and estrogen, and under serum-free conditions. The isoprenoids farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) significantly reverse atorvastatin-induced inhibition of Tsc2^–/– cell growth, suggesting that atorvastatin dually targets a farnesylated protein, such as Rheb, and a geranylgeranylated protein, such as Rho, both of which have elevated activity in Tsc2^–/– cells. Atorvastatin reduced Rheb isoprenylation, GTP loading, and membrane localization. Atorvastatin also inhibited the constitutive phosphorylation of mammalian target of rapamycin, S6 kinase, and S6 found in Tsc2^–/– cells in an FPP-reversible manner and attenuated the high levels of phosphorylated S6 in Tsc2-heterozygous mice. Atorvastatin, but not rapamycin, attenuated the increased levels of activated RhoA in Tsc2^–/– cells, and this was reversed by GGPP. These results suggest that atorvastatin may inhibit both rapamycin-sensitive and rapamycin-insensitive mechanisms of tuberin-null cell growth, likely via Rheb and Rho inhibition, respectively. Atorvastatin may have potential therapeutic benefit in TSC syndromes, including LAM. [Cancer Res 2007;67(20):9878–86]

This article has been cited by other articles:

				I. J. Rzepczynska, P. C. Piotrowski, D. H. Wong, A. B. Cress, J. Villanueva, and A. J. Duleba Role of Isoprenylation in Simvastatin-Induced Inhibition of Ovarian Theca-Interstitial Growth in the Rat Biol Reprod, November 1, 2009; 81(5): 850 - 855. [Abstract] [Full Text] [PDF]

				S. El-Chemaly, A. Taveira-DaSilva, M. P. Stylianou, and J. Moss Statins in lymphangioleiomyomatosis: a word of caution Eur. Respir. J., August 1, 2009; 34(2): 513 - 514. [Full Text] [PDF]

				G. A. Finlay, A. J. Malhowski, K. Polizzi, I. Malinowska-Kolodziej, and D. J. Kwiatkowski Renal and liver tumors in Tsc2+/- mice, a model of tuberous sclerosis complex, do not respond to treatment with atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor Mol. Cancer Ther., July 1, 2009; 8(7): 1799 - 1807. [Abstract] [Full Text] [PDF]

				J. Woodard, A. Sassano, N. Hay, and L. C. Platanias Statin-Dependent Suppression of the Akt/Mammalian Target of Rapamycin Signaling Cascade and Programmed Cell Death 4 Up-Regulation in Renal Cell Carcinoma Clin. Cancer Res., July 15, 2008; 14(14): 4640 - 4649. [Abstract] [Full Text] [PDF]