ROSUVASTATIN ACTING AS A DEMETHYLATING AGENT AFFECTS PROLIFERATION OF TSC2-/meth ASM CELLS

Tuberous sclerosis complex (TSC) is a multi-systemic syndrome caused by mutations in TSC1 or TSC2 gene. TSC2-/- and TSC2-/meth smooth muscle (ASM) cells do not express tuberin and bear loss of heterozigosity caused by a double hit on TSC2 or by methylation of TSC2 promoter, respectively. In TSC2-null cells Rheb is constitutively activated. Statins inhibit the HMG-CoA reductase, which is regulated by mevalonate formation, and block the synthesis of isoprenoid lipids inhibiting the farnesylation of Rheb and the geranylgeranylation of RhoA. Rosuvastatin affected TSC2-/meth ASM cell growth but did not altered TSC2-/- ASM cell proliferation. Moreover rosuvastatin inhibited activated RhoA level in TSC2-/meth ASM cells, while in TSC2-/- ASM cells it was effective only as adjuvant of the specific mTOR inhibitor rapamycin. Rosuvastatin, acting as a demethylating agent, induced tuberin expression in TSC2-/meth ASM cells alone and in co-treatment with 5-azacytidine while did not affect tuberin expression in TSC-/- ASM cells. In presence of rapamycin, rosuvastatin is more effective in inhibiting ERK and S6 phosphorylation in TSC2-/- and TSC2-/methASM cells. These data indicate that rosuvastatin may be used as an adjunct to rapamycin therapy in TSC with a specific activity in TSC2 cells with epigenetic modification likely demethylating TSC2 promoter.