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Insulin Protects Cardiac Myocytes from Doxorubicin Toxicity by Sp1-Mediated Transactivation of Survivin

Authors
 Beom Seob Lee  ;  Jaewon Oh  ;  Sung Ku Kang  ;  Sungha Park  ;  Sang-Hak Lee  ;  Donghoon Choi  ;  Ji Hyung Chung  ;  Youn Wook Chung  ;  Seok-Min Kang 
Citation
 PLOS ONE, Vol.10(8) : e0135438, 2015 
Journal Title
PLOS ONE
Issue Date
2015
MeSH
Animals ; Cell Line, Tumor ; Cell Survival/drug effects ; Chromatin Immunoprecipitation ; Doxorubicin/pharmacology* ; Insulin/pharmacology* ; Microscopy, Confocal ; Microtubule-Associated Proteins/metabolism ; Myocytes, Cardiac/drug effects* ; RNA Interference ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Sp1 Transcription Factor/metabolism*
Abstract
Insulin inhibits ischemia/reperfusion-induced myocardial apoptosis through the PI3K/Akt/mTOR pathway. Survivin is a key regulator of anti-apoptosis against doxorubicin-induced cardiotoxicity. Insulin increases survivin expression in cardiac myocytes to mediate cytoprotection. However, the mechanism by which survivin mediates the protective effect of insulin against doxorubicin-associated injury remains to be determined. In this study, we demonstrated that pretreatment of H9c2 cardiac myocytes with insulin resulted in a significant decrease in doxorubicin-induced apoptotic cell death by reducing cytochrome c release and caspase-3 activation. Doxorubicin-induced reduction of survivin mRNA and protein levels was also significantly perturbed by insulin pretreatment. Reducing survivin expression with survivin siRNA abrogated insulin-mediated inhibition of caspase-3 activation, suggesting that insulin signals to survivin inhibited caspase-3 activation. Interestingly, pretreatment of H9c2 cells with insulin or MG132, a proteasome inhibitor, inhibited doxorubicin-induced degradation of the transcription factor Sp1. ChIP assay showed that pretreatment with insulin inhibited doxorubicin-stimulated Sp1 dissociation from the survivin promoter. Finally using pharmacological inhibitors of the PI3K pathway, we showed that insulin-mediated activation of the PI3K/Akt/mTORC1 pathway prevented doxorubicin-induced proteasome-mediated degradation of Sp1. Taken together, insulin pretreatment confers a protective effect against doxorubicin-induced cardiotoxicity by promoting Sp1-mediated transactivation of survivin to inhibit apoptosis. Our study is the first to define a role for survivin in cellular protection by insulin against doxorubicin-associated injury and show that Sp1 is a critical factor in the transcriptional regulation of survivin.
Files in This Item:
T201503042.pdf Download
DOI
10.1371/journal.pone.0135438
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kang, Seok Min(강석민) ORCID logo https://orcid.org/0000-0001-9856-9227
Park, Sung Ha(박성하) ORCID logo https://orcid.org/0000-0001-5362-478X
Oh, Jae Won(오재원) ORCID logo https://orcid.org/0000-0002-4585-1488
Lee, Beom Seob(이범섭)
Lee, Sang Hak(이상학) ORCID logo https://orcid.org/0000-0002-4535-3745
Chung, Youn Wook(정연욱) ORCID logo https://orcid.org/0000-0002-4382-1410
Choi, Dong Hoon(최동훈) ORCID logo https://orcid.org/0000-0002-2009-9760
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140885
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