Chromatin remodelling by rosuvastatin normalizes TSC2-/meth cell phenotype through the expression of tuberin
Articolo
Data di Pubblicazione:
2013
Citazione:
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: THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - 345:2(2013 May), pp. 180-188. [10.1124/jpet.113.203141]
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
HMG-COA reductase; cytokine production; sclerosis complex; renal angiomyolipoma; colorectal-cancer; breast-cancer; growth-factor; statins; inhibition; rapamycin
Elenco autori:
E. Lesma, S. Ancona, E. Orpianesi, V. Grande, A.M. Di Giulio, A. Gorio
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