Doxorubicin-induced p53 interferes with mitophagy in cardiac fibroblasts

Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac...

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Published in:	PloS one Vol. 15; no. 9; p. e0238856
Main Authors:	Mancilla, T R, Davis, L R, Aune, G J
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 22-09-2020 Public Library of Science (PLoS)
Subjects:	Animals Anthracycline Antibiotics, Antineoplastic - pharmacology Anticancer properties Biology and Life Sciences Cancer Cardiomyopathy Cardiotoxicity Cardiotoxicity - pathology Cardiotoxicity - prevention & control Cell adhesion & migration Cell cycle Cell migration Cellular stress response Chemotherapy Childhood cancer Children Chronic fatigue syndrome Complications and side effects Coronary artery disease Critical components Cytotoxicity Damage Deoxyribonucleic acid Dilated cardiomyopathy DNA DNA damage Doxorubicin Doxorubicin - pharmacology Drug therapy Extracellular matrix Fibroblasts Fibroblasts - drug effects Fibroblasts - metabolism Fibroblasts - pathology Flow cytometry Gene expression Genetic aspects Health aspects Heart Heart cells Heart diseases Injury prevention Laboratory animals Localization Medical research Medical treatment Medicine and Health Sciences Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Mitochondria - drug effects Mitochondria - metabolism Mitochondria - pathology Mitochondrial DNA Mitophagy Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology p53 Protein Parkin protein Pediatric research Pediatrics Physiological aspects Quality of life Research and Analysis Methods Risk factors Tumor proteins Tumor Suppressor Protein p53 - physiology United States United States > US
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Summary:	Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/- cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/- cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors.
Bibliography:	Competing Interests: NO authors have competing interest.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0238856