TY - JOUR
T1 - Statins in lymphangioleiomyomatosis
T2 - Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling
AU - Atochina-Vasserman, Elena N.
AU - Goncharov, Dmitry A.
AU - Volgina, Alla V.
AU - Milavec, Megan
AU - James, Melane L.
AU - Krymskaya, Vera P.
PY - 2013/11
Y1 - 2013/11
N2 - 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.
AB - 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.
KW - Apoptosis
KW - LAM
KW - MTOR
KW - TSC
KW - TSC2
UR - http://www.scopus.com/inward/record.url?scp=84887052370&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887052370&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2013-0203RC
DO - 10.1165/rcmb.2013-0203RC
M3 - Article
C2 - 23947572
AN - SCOPUS:84887052370
VL - 49
SP - 704
EP - 709
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 5
ER -