Tuberous sclerosis complex (TSC) is a multi-systemic syndrome caused by mutations in TSC1 or TSC2 gene. In TSC2-null cells, Rheb, a member of the Ras family of GTPases, is constitutively activated. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase and block the synthesis of isoprenoid lipids with inhibition of Rheb farnesylation and RhoA geranylgeranylation. The effects of rosuvastatin on the function of human TSC2(-/-) and TSC2(-/meth) α-actin smooth muscle (ASM) cells have been investigated. The TSC2(-/-) and TSC2(-/meth) ASM cells, previously isolated in our laboratory from the renal angiomyolipoma of two TSC patients, do not express tuberin and bear loss of heterozigosity caused by a double hit on TSC2 and methylation of TSC2 promoter, respectively. Exposure to rosuvastatin affected TSC2(-/meth) ASM cell growth and promoted tuberin expression by acting as a demethylating agent. This occurred without changes in interleukin release. Rosuvastatin also reduced RhoA activation in TSC2(-/meth) ASM cells, and it required coadministration with the specific mTOR (mammalian target of rapamycin) inhibitor rapamycin to be effective in TSC2(-/-) ASM cells. Rapamycin enhanced rosuvastatin effect in inhibiting cell proliferation in TSC2(-/-) and TSC2(-/meth) ASM cells. Rosuvastatin alone did not alter phosphorylation of S6 and extracellular signal-regulated kinase (ERK), and at the higher concentration, rosuvastatin and rapamycin slightly decreased ERK phosphorylation. These results suggest that rosuvastatin may potentially represent a treatment adjunct to the therapy with mTOR inhibitors now in clinical development for TSC. In particular, rosuvastatin appears useful when the disease is originated by epigenetic defects.
Chromatin remodelling by rosuvastatin normalizes TSC2-/meth cell phenotype through the expression of tuberin / E. Lesma, S. Ancona, E. Orpianesi, V. Grande, A.M. Di Giulio, A. Gorio. - In: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - 345:2(2013 May), pp. 180-188.
|Titolo:||Chromatin remodelling by rosuvastatin normalizes TSC2-/meth cell phenotype through the expression of tuberin|
LESMA, ELENA ANNA (Primo)
ANCONA, SILVIA (Secondo)
DI GIULIO, ANNA MARIA (Penultimo)
GORIO, ALFREDO (Ultimo)
|Parole Chiave:||HMG-COA reductase; cytokine production; sclerosis complex; renal angiomyolipoma; colorectal-cancer; breast-cancer; growth-factor; statins; inhibition; rapamycin|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||mag-2013|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1124/jpet.113.203141|
|Appare nelle tipologie:||01 - Articolo su periodico|