Insulin protects cardiac myocytes from doxorubicin toxicity by Sp1-mediated transactivation of survivin

Beom Seob Lee, Jaewon Oh, Sung Ku Kang, Sungha Park, Sang Hak Lee, Donghoon Choi, Ji Hyung Chung, Youn Wook Chung, seokmin kang

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 proteasomemediated 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.

Original languageEnglish
Article numbere0135438
JournalPloS one
Volume10
Issue number8
DOIs
Publication statusPublished - 2015 Aug 13

Fingerprint

doxorubicin
transcriptional activation
Cardiac Myocytes
Doxorubicin
Transcriptional Activation
Toxicity
insulin
Insulin
toxicity
pretreatment
phosphatidylinositol 3-kinase
caspase-3
Chemical activation
Phosphatidylinositol 3-Kinases
Caspase 3
apoptosis
Apoptosis
protective effect
cardiomyocytes
transcription factors

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lee, Beom Seob ; Oh, Jaewon ; Kang, Sung Ku ; Park, Sungha ; Lee, Sang Hak ; Choi, Donghoon ; Chung, Ji Hyung ; Chung, Youn Wook ; kang, seokmin. / Insulin protects cardiac myocytes from doxorubicin toxicity by Sp1-mediated transactivation of survivin. In: PloS one. 2015 ; Vol. 10, No. 8.
@article{012ce85d9883463499ad329f59c1e343,
title = "Insulin protects cardiac myocytes from doxorubicin toxicity by Sp1-mediated transactivation of survivin",
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 proteasomemediated 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.",
author = "Lee, {Beom Seob} and Jaewon Oh and Kang, {Sung Ku} and Sungha Park and Lee, {Sang Hak} and Donghoon Choi and Chung, {Ji Hyung} and Chung, {Youn Wook} and seokmin kang",
year = "2015",
month = "8",
day = "13",
doi = "10.1371/journal.pone.0135438",
language = "English",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8",

}

Insulin protects cardiac myocytes from doxorubicin toxicity by Sp1-mediated transactivation of survivin. / Lee, Beom Seob; Oh, Jaewon; Kang, Sung Ku; Park, Sungha; Lee, Sang Hak; Choi, Donghoon; Chung, Ji Hyung; Chung, Youn Wook; kang, seokmin.

In: PloS one, Vol. 10, No. 8, e0135438, 13.08.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Insulin protects cardiac myocytes from doxorubicin toxicity by Sp1-mediated transactivation of survivin

AU - Lee, Beom Seob

AU - Oh, Jaewon

AU - Kang, Sung Ku

AU - Park, Sungha

AU - Lee, Sang Hak

AU - Choi, Donghoon

AU - Chung, Ji Hyung

AU - Chung, Youn Wook

AU - kang, seokmin

PY - 2015/8/13

Y1 - 2015/8/13

N2 - 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 proteasomemediated 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.

AB - 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 proteasomemediated 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.

UR - http://www.scopus.com/inward/record.url?scp=84942944561&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942944561&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0135438

DO - 10.1371/journal.pone.0135438

M3 - Article

C2 - 26271039

AN - SCOPUS:84942944561

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 8

M1 - e0135438

ER -