RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation.
Osteosarcoma is the most common primary bone tumour in young adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of osteosarcoma treatment. The identification of signals that promote apoptosis may provide clues to develop new therapeutic strategies for chemoresistant osteosarcoma. Here, we show that lipophilic statins (atorvastatin, simvastatin, cerivastatin) markedly induce caspases-dependent apoptosis in various human osteosarcoma cells, independently of bone morphogenetic protein (BMP)-2 signaling and cell differentiation. Although statins increased BMP-2 expression, the proapoptotic effect of statins was not prevented by the BMP antagonist noggin, and was abolished by mevalonate and geranylgeranylpyrophosphate, suggesting the involvement of defective protein geranylgeranylation. Consistently, lipophilic statins induced membrane RhoA relocalization to the cytosol and inhibited RhoA activity, which resulted in decreased phospho-p42/p44- mitogen-activated protein kinases (MAPKs) and Bcl-2 levels. Constitutively active RhoA rescued phospho-p42/p44-MAPKs and Bcl-2 and abolished statin-induced apoptosis. Thus, lipophilic statins induce caspase-dependent osteosarcoma cell apoptosis by a RhoA-p42/p44 MAPKs-Bcl-2-mediated mechanism, independently of BMP-2 signaling and cell differentiation.
INSERM U606, University Paris 7, IFR 139, Lariboisière Hospital, 2 rue Ambroise Paré, 75475 Paris Cedex 10, France.
O
O
Fromigué
E
E
Haÿ
D
D
Modrowski
S
S
Bouvet
A
A
Jacquel
P
P
Auberger
P J
PJ
Marie
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000924:Anticholesteremic Agents; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D006538:Heptanoic Acids; D011106:Polyisoprenyl Phosphates; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D000069059:Atorvastatin; D019821:Simvastatin; C086276:cerivastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D020169:Caspases; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate