Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation.
Lymphangioleiomyomatosis (LAM), a rare pulmonary disorder, manifests as an abnormal neoplastic growth of smooth muscle-like cells within the lungs. Mutational inactivation of tumor suppressor tuberous sclerosis complex 2 (TSC2) in LAM constitutively activates the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) signaling pathway and promotes neoplastic growth of LAM cells. In many cell types, type I interferon beta (IFNbeta) inhibits proliferation and induces apoptosis through signal transducers and activators of transcription (STAT)-dependent and STAT-independent signaling pathways, one of which is the mTOR/S6K1 signaling pathway. Our study shows that IFNbeta is expressed in LAM tissues and LAM-derived cell cultures; however, IFNbeta attenuates LAM-derived cell proliferation only at high concentrations, 100 and 1000 U/ml (IC(50) value for IFNbeta is 20 U/ml compared with 1 U/ml for normal human mesenchymal cells, human bronchus fibroblasts and human airway smooth muscle cells). Likewise, IFNbeta only attenuates proliferation of smooth muscle TSC2-null ELT3 cells. Analysis of IFNbeta signaling in LAM cells showed expression of IFNbeta receptor alpha (IFNbetaRalpha) and IFNbetaRbeta, activation and nuclear translocation of STAT1, and phosphorylation of STAT3 and p38 mitogen-activated protein kinase (MAPK), but IFNbeta had little effect on S6K1 activity. However, the re-expression of TSC2 or inhibition of mTOR/S6K1 with rapamycin (sirolimus) augmented antiproliferative effects of IFNbeta in LAM and TSC2-null ELT3 cells. Our study demonstrates that IFNbeta-dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2-dependent inhibition of mTOR/S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation.
Goncharova
Elena A
EA
Department of Medicine, University of Pennsylvania, TRL Suite 1200, 125 South 31st Street, Philadelphia, PA 19104, USA. goncharo@mail.med.upenn.edu
Goncharov
Dmitry A
DA
Chisolm
Amelia
A
Spaits
Matthew S
MS
Lim
Poay N
PN
Cesarone
Gregory
G
Khavin
Irene
I
Tliba
Omar
O
Amrani
Yassine
Y
Panettieri
Reynold A
RA
Krymskaya
Vera P
VP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D016899:Interferon-beta / Q000378:metabolism / Q000494:pharmacology*; D007889:Leiomyoma / Q000473:pathology*; D018192:Lymphangioleiomyomatosis / Q000378:metabolism* / Q000473:pathology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017471:Receptors, Interferon / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013223:Statistics as Topic; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014594:Uterine Neoplasms / Q000473:pathology*
D017471:Receptors, Interferon; C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D016899:Interferon-beta; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus