BMP-Id pathway targeted by cholesterol myristate suppresses the apoptosis of PC12 cells.
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, β-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.
The State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, Nanjing University, Nanjing, China. CDF27212@21cn.com
Dong-Feng
DF
Chen
Jia-hui
JH
Cao
Yang
Y
Liu
Yiling
Y
Wu
Shao-Hui
SH
Du
Hui
H
Li
Jian-Hong
JH
Zhou
Yi-Wei
YW
Li
He-Ping
HP
Zeng
Zi-Chun
ZC
Hua
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D055415:Bone Morphogenetic Protein 4 / Q000276:immunology / Q000378:metabolism*; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D002784:Cholesterol / Q000494:pharmacology*; D016895:Culture Media, Serum-Free / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D019814:Myristic Acid / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection / Q000379:methods
D000906:Antibodies; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D016895:Culture Media, Serum-Free; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D012333:RNA, Messenger; D019814:Myristic Acid; D002784:Cholesterol; D052004:Bone Morphogenetic Protein Receptors