Doxorubicin-Induced p53 Interferes with Mitophagy in Cardiac Fibroblasts

Abstract

Doxorubicin is a mainstay in pediatric chemotherapy treatment because of its efficacy treating leukemia and lymphoma. Unfortunately, every childhood cancer survivor will develop a chronic health problem, one of the most serious being cardiac disease. How doxorubicin damages the heart in such a way that disease progression occurs over multiple decades is still not understood.\n\nThe dose of doxorubicin selected does not cause apoptosis but does arrest cell cycle. It also decreases the cells ability to migrate. Gene profiling indicated a cardiac remodeling and inflammatory profile. Mitochondria increased ROS production and underwent membrane depolarization. Secondly, the Parkin:p53 interaction mechanism was investigated. Doxorubicin was found to increase p53 expression and it was shown to sequester Parkin. As a result, mitophagy in doxorubicin-treated cells was decreased. Lastly, cardiac fibroblasts were isolated from p53-/- mice and treated with doxorubicin. The gene expression phenotype in these cells was attenuated and migration was restored. Proliferation was still decreased. Mitochondrial dysfunction was also partially attenuated. Without p53, Parkin could now localize to the mitochondria and mitophagy was restored.\n\nDoxorubicin induces a deleterious phenotype in cardiac fibroblasts that may be due to the interaction between two stress responses caused by doxorubicins DNA and mitochondrial damage. Cardiac fibroblasts are a viable target and further research needs to be done to elucidate other harmful mechanisms at play in the fibroblast. Knowledge about the importance of cardiac fibroblasts in the development of doxorubicin-induced cardiotoxicity and a pathological mechanism broadens our understanding and ability to develop protective therapies to improve the quality of life of cancer survivors.\n\nThe project described was supported by all of the following sources for GJA: O_LISt. Baldricks Foundation Scholar (Career Development Award)\nC_LIO_LITurn it Gold Foundation\nC_LI The project described was supported by all of the following sources for TRM:\n\nO_LINIH T32GM113896 (STX-MSTP) award\nC_LIO_LINational Center for Advancing Translational Science, NIH through grant TL1 TR001119. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.\nC_LI