Imperial College London
Alternate

ProfessorCharlesCoombes

Faculty of Medicine, Department of Surgery & Cancer

Emeritus Professor of Medical Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2135c.coombes

 
 
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Assistant

 

Mrs Suzy Ford +44 (0)20 7594 2135

 
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Location

 

145ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Roca-Alonso:2015:10.1038/cddis.2015.89,
author = {Roca-Alonso, L and Castellano, L and Mills, A and Dabrowska, AF and Sikkel, MB and Pellegrino, L and Jacob, J and Frampton, AE and Krell, J and Coombes, RC and Harding, SE and Lyon, AR and Stebbing, J},
doi = {10.1038/cddis.2015.89},
journal = {Cell Death & Disease},
title = {Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in beta-adrenergic signaling and enhances apoptosis},
url = {http://dx.doi.org/10.1038/cddis.2015.89},
volume = {6},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks ofcardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typicallyprogresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development ofcardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles inboth cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellularprocesses downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application toisolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts followingmyocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating theβ-adrenergic pathway, where preferential β1- and β2-adrenoceptor (β1AR and β2AR) direct inhibition is combined with Giα-2targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, wedemonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygenspecies generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. Inconclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotectiveand anti-tumorigenic strategy for anthracyclines.
AU  - Roca-Alonso,L
AU  - Castellano,L
AU  - Mills,A
AU  - Dabrowska,AF
AU  - Sikkel,MB
AU  - Pellegrino,L
AU  - Jacob,J
AU  - Frampton,AE
AU  - Krell,J
AU  - Coombes,RC
AU  - Harding,SE
AU  - Lyon,AR
AU  - Stebbing,J
DO  - 10.1038/cddis.2015.89
PY  - 2015///
SN  - 2041-4889
TI  - Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in beta-adrenergic signaling and enhances apoptosis
T2  - Cell Death & Disease
UR  - http://dx.doi.org/10.1038/cddis.2015.89
UR  - http://hdl.handle.net/10044/1/28657
VL  - 6
ER  -
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