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Chromatin remodeling by rosuvastatin normalizes TSC2-/meth cell phenotype through the expression of tuberin

Elena Lesma1, Silvia Ancona, Emanuela Orpianesi

  • 1Laboratories of Pharmacology, Department of Health Sciences, Università degli Studi di Milano, via di Rudini', 8, 20142 Milano, Italy. elena.lesma@unimi.it

The Journal of Pharmacology and Experimental Therapeutics
|February 22, 2013
PubMed

Insights

Rosuvastatin may help treat tuberous sclerosis complex (TSC), especially when caused by epigenetic defects. It shows promise as an add-on therapy with mTOR inhibitors by affecting cell growth and gene expression in TSC2-deficient cells.

Area of Science:

  • Cell Biology
  • Genetics
  • Pharmacology

Background:

  • Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 genes, leading to uncontrolled cell growth.
  • In TSC2-deficient cells, Rheb GTPase is constitutively active, driving cellular proliferation.
  • Statins, like rosuvastatin, inhibit HMG-CoA reductase, impacting isoprenoid synthesis and potentially modulating Rheb and RhoA activity.

Purpose of the Study:

  • To investigate the effects of rosuvastatin on human TSC2-null (TSC2(-/-)) and TSC2-methylated (TSC2(-/meth)) smooth muscle cells.
  • To explore rosuvastatin's potential as an adjunct therapy for TSC, particularly in cases with epigenetic defects.

Main Methods:

  • Cultured human TSC2(-/-) and TSC2(-/meth) alpha-actin smooth muscle cells derived from TSC patients.
  • Treated cells with rosuvastatin alone or in combination with the mTOR inhibitor rapamycin.
  • Assessed cell growth, tuberin expression, interleukin release, RhoA activation, and phosphorylation of S6 and ERK.

Main Results:

  • Rosuvastatin promoted tuberin expression and affected cell growth in TSC2(-/meth) cells, acting as a demethylating agent without altering IL release.
  • Rosuvastatin reduced RhoA activation in TSC2(-/meth) cells; its efficacy in TSC2(-/-) cells required co-administration with rapamycin.
  • Combined rosuvastatin and rapamycin inhibited cell proliferation in both cell types and slightly decreased ERK phosphorylation at higher concentrations.

Conclusions:

  • Rosuvastatin demonstrates therapeutic potential as an adjunct to mTOR inhibitors for TSC treatment, especially in TSC originating from epigenetic defects.
  • The drug's ability to modulate tuberin expression and cell signaling pathways in TSC cells warrants further investigation for clinical application.

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