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
- PMID: 17942919
- DOI: 10.1158/0008-5472.CAN-07-1394
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
Abstract
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.
Similar articles
-
Measurements of TSC2 GAP activity toward Rheb.Methods Enzymol. 2006;407:46-54. doi: 10.1016/S0076-6879(05)07005-9. Methods Enzymol. 2006. PMID: 16757313
-
The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb.Novartis Found Symp. 2004;262:148-54; discussion 154-9, 265-8. Novartis Found Symp. 2004. PMID: 15562827 Review.
-
Farnesylthiosalicylic acid (salirasib) inhibits Rheb in TSC2-null ELT3 cells: a potential treatment for lymphangioleiomyomatosis.Int J Cancer. 2012 Mar 15;130(6):1420-9. doi: 10.1002/ijc.26139. Epub 2011 Aug 1. Int J Cancer. 2012. PMID: 21500191
-
Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex.Eur J Hum Genet. 2005 Jan;13(1):59-68. doi: 10.1038/sj.ejhg.5201276. Eur J Hum Genet. 2005. PMID: 15483652
-
Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase.Oncogene. 2006 Oct 16;25(48):6361-72. doi: 10.1038/sj.onc.1209882. Oncogene. 2006. PMID: 17041622 Review.
Cited by
-
Possible Novel Therapeutic Targets in Lymphangioleiomyomatosis Treatment.Front Med (Lausanne). 2020 Sep 24;7:554134. doi: 10.3389/fmed.2020.554134. eCollection 2020. Front Med (Lausanne). 2020. PMID: 33072782 Free PMC article. Review.
-
The Antitumor Effect of Lipophilic Bisphosphonate BPH1222 in Melanoma Models: The Role of the PI3K/Akt Pathway and the Small G Protein Rheb.Int J Mol Sci. 2019 Oct 3;20(19):4917. doi: 10.3390/ijms20194917. Int J Mol Sci. 2019. PMID: 31623406 Free PMC article.
-
Role of mammalian target of rapamycin signaling pathway in regulation of fatty acid oxidation in a preeclampsia-like mouse model treated with pravastatin.Chin Med J (Engl). 2019 Mar 20;132(6):671-679. doi: 10.1097/CM9.0000000000000129. Chin Med J (Engl). 2019. PMID: 30855348 Free PMC article.
-
Pulmonary hypertension associated with neurofibromatosis type 1.Eur Respir Rev. 2018 Aug 29;27(149):180053. doi: 10.1183/16000617.0053-2018. Print 2018 Sep 30. Eur Respir Rev. 2018. PMID: 30158278 Free PMC article. Review.
-
Assessment of Response of Kidney Tumors to Rapamycin and Atorvastatin in Tsc1+/- Mice.Transl Oncol. 2017 Oct;10(5):793-799. doi: 10.1016/j.tranon.2017.07.009. Epub 2017 Aug 24. Transl Oncol. 2017. PMID: 28844017 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Miscellaneous