Statins in lymphangioleiomyomatosis: Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling

Elena N. Atochina-Vasserman, Dmitry A. Goncharov, Alla V. Volgina, Megan Milavec, Melane L. James, Vera P. Krymskaya

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Mutations of the tumor suppressor genes tuberous sclerosis complex (TSC)1 andTSC2 causepulmonarylymphangioleiomyomatosis (LAM) and tuberous sclerosis (TS). Current rapamycin-based therapies for TS and LAM have a predominantly cytostatic effect, and disease progression resumes with therapy cessation. Evidence of RhoA GTPase activation in LAM-derived and human TSC2-null cells suggests that 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor statins can be used as potential adjuvant agents. The goal of this studywas to determinewhich statin (simvastatin or atorvastatin) is more effective in suppressing TSC2-null cell growth and signaling. Simvastatin, but not atorvastatin, showed a concentrationdependent (0.5-10 μM) inhibitory effect on mouse TSC2-null and human LAM-derived cell growth. Treatment with 10 μM simvastatin induced dramatic disruption of TSC2-null cell monolayer and cell rounding; in contrast, few changes were observed in cells treated with the same concentration of atorvastatin. Combined treatment of rapamycin with simvastatin but not with atorvastatin showed a synergistic growth-inhibitory effect on TSC2-null cells. Simvastatin, but not atorvastatin, inhibitedthe activity of prosurvival serine-threonine kinase Akt and induced marked up-regulation of cleaved caspase-3, a marker of cell apoptosis. Simvastatin, but not atorvastatin, also induced concentration-dependent inhibition of p42/p44 Erk and mTORC1. Thus, our data show growth-inhibitory and proapoptotic effects of simvastatin on TSC2-null cells compared with atorvastatin. These findings have translational significance for combinatorial therapeutic strategies of simvastatin to inhibit TSC2- null cell survival in TS and LAM.

Original languageEnglish
Pages (from-to)704-709
Number of pages6
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume49
Issue number5
DOIs
Publication statusPublished - Nov 2013
Externally publishedYes

Keywords

  • Apoptosis
  • LAM
  • MTOR
  • TSC
  • TSC2

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

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