{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T21:22:45Z","timestamp":1791062565091,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2013,11,1]],"date-time":"2013-11-01T00:00:00Z","timestamp":1383264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mutations of the tumor suppressor genes tuberous sclerosis complex(TSC)1 and TSC2 cause pulmonary lymphangioleiomyomatosis (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 study was to determine which statin (simvastatin or atorvastatin) is more effective in suppressing TSC2-null cell growth and signaling. Simvastatin, but not atorvastatin, showed a concentration-dependent (0.5\u201310 \u03bcM) inhibitory effect on mouse TSC2-null and human LAM\u2013derived cell growth. Treatment with 10 \u03bcM 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, inhibited the 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.<\/jats:p>","DOI":"10.1165\/rcmb.2013-0203rc","type":"journal-article","created":{"date-parts":[[2013,8,15]],"date-time":"2013-08-15T15:09:37Z","timestamp":1376579377000},"page":"704-709","source":"Crossref","is-referenced-by-count":26,"title":["Statins in Lymphangioleiomyomatosis. Simvastatin and Atorvastatin Induce Differential Effects on\n                    <i>tuberous sclerosis complex 2<\/i>\n                    \u2013Null Cell Growth and Signaling"],"prefix":"10.1093","volume":"49","author":[{"given":"Elena N.","family":"Atochina-Vasserman","sequence":"first","affiliation":[{"name":"Airway Biology Initiative, Pulmonary, Allergy & Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry A.","family":"Goncharov","sequence":"additional","affiliation":[{"name":"Airway Biology Initiative, Pulmonary, Allergy & Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alla V.","family":"Volgina","sequence":"additional","affiliation":[{"name":"Airway Biology Initiative, Pulmonary, Allergy & Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Milavec","sequence":"additional","affiliation":[{"name":"Airway Biology Initiative, Pulmonary, Allergy & Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melane L.","family":"James","sequence":"additional","affiliation":[{"name":"Airway Biology Initiative, Pulmonary, Allergy & Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera P.","family":"Krymskaya","sequence":"additional","affiliation":[{"name":"Airway Biology Initiative, Pulmonary, Allergy & Critical Care Division, 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