RESUMO
Identifying small molecules that suppress apoptosis is promising for the therapy of brain diseases. We recently showed that autocrine bone morphogenetic protein (BMP) signaling involves the effects of cholesterol myristate present in traditional Chinese medicine on mesenchymal stem cells. The present study evaluated the effects of cholesterol myristate on the apoptosis and BMP signaling of PC12 cells. PC12 cells transfected by the inhibitor of differentiation (Id1) promoter reporter construct target gene of BMP4 signaling; cholesterol myristate increases the activity of Id1 promoter. However, structurally related steroids such as cholesterol, ß-sitosterol and cholesten-3-one, lack of the myristate, did not affect the activity of Id1 promoter, suggesting that myristate is essential for the effect of cholesterol myristate. These effects depend on BMP signaling. Apoptosis analysis indicated that cholesterol myristate inhibited the apoptosis of PC12 cells induced in serum-free condition. Cholesterol myristate significantly increases the expression of BMP4, BMPRIA, p-Smad1/5/8, Id1 and its antiapoptotic target gene Bcl-xL in PC12 cells treated in serum-free condition. Moreover, BMP antagonist reduced the anti-apoptotic effect of cholesterol myristate. Thus, this study is to provide evidence that BMP-Id pathway targeted by cholesterol myristate suppresses the apoptosis of PC12 cells. Our findings are therefore of considerable therapeutic significance and provide the potential of newly exploiting cholesterol myristate and clinically in brain disease therapies.
Assuntos
Apoptose/efeitos dos fármacos , Proteína Morfogenética Óssea 4/metabolismo , Colesterol/farmacologia , Proteína 1 Inibidora de Diferenciação/metabolismo , Ácido Mirístico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos/farmacologia , Proteína Morfogenética Óssea 4/imunologia , Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Meios de Cultura Livres de Soro/efeitos adversos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Mirístico/química , Células PC12 , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro , Ratos , Fatores de Tempo , Transfecção/métodosRESUMO
Bone morphogenetic proteins (BMPs) were first studied as growth factors or morphogens of the transforming growth factor-beta superfamily. These growth molecules, originally associated with bone and cartilage development, are now known to play an important role in morphogenesis and homeostasis in many other tissues. More recently, significant contributions from BMPs, their receptors, and interacting molecules have been linked to carcinogenesis and tumor progression. On the other hand, BMPs can sometimes function as a tumor suppressor. Our report highlights these new roles in the pathogenesis of cancer that may suggest novel targets for therapeutic intervention.