ArticleJournal of molecular and cellular cardiology2014
Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21(Cip1.).
Article in Journal of molecular and cellular cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 27 citations in OpenAlex.
- Marein Alleviates Doxorubicin-Induced Cardiotoxicity through FAK/AKT Pathway Modulation while Potentiating its Anticancer Activity.Cardiovascular toxicology · 2024Article
- Article
- Upregulation of Biomarker Limd1 Was Correlated with Immune Infiltration in Doxorubicin-Related Cardiotoxicity.Mediators of inflammation · 2023Article
- Cardiotoxicity of Cancer Treatments: Focus on Anthracycline Cardiomyopathy.Arteriosclerosis, thrombosis, and vascular biology · 2021Review
- Ceramide launches an acute anti-adhesion pro-migration cell signaling program in response to chemotherapy.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Doxorubicin induces cardiomyocyte apoptosis and atrophy through cyclin-dependent kinase 2-mediated activation of forkhead box O1.The Journal of biological chemistry · 2020Article
- The circadian clock protects against ionizing radiation-induced cardiotoxicity.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Cell adhesion to collagen promotes leukemia resistance to doxorubicin by reducing DNA damage through the inhibition of Rac1 activation.Scientific reports · 2019Article
- Cell Cycle Proteins as Key Regulators of Postmitotic Cell Death.The Yale journal of biology and medicine · 2019Review
- Genome-Wide RNAi Screen Identifies Regulators of Cardiomyocyte Necrosis.ACS pharmacology & translational science · 2019Article
- Inhibition of cyclin-dependent kinase 2 protects against doxorubicin-induced cardiomyocyte apoptosis and cardiomyopathy.The Journal of biological chemistry · 2018Article
- FAK and S6K1 Inhibitor, Neferine, Dually Induces Autophagy and Apoptosis in Human Neuroblastoma Cells.Molecules (Basel, Switzerland) · 2018Article
- Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth.The Journal of biological chemistry · 2017Article
- Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity.Cardiovascular research · 2016Article
- Extracellular Matrix-Mediated Maturation of Human Pluripotent Stem Cell-Derived Cardiac Monolayer Structure and Electrophysiological Function.Circulation. Arrhythmia and electrophysiology · 2016Article
- Signaling Pathways in Cardiac Myocyte Apoptosis.BioMed research international · 2016Review
- Inhibition of Diaphanous Formin Signaling In Vivo Impairs Cardiovascular Development and Alters Smooth Muscle Cell Phenotype.Arteriosclerosis, thrombosis, and vascular biology · 2015Article
- GRAF1 deficiency blunts sarcolemmal injury repair and exacerbates cardiac and skeletal muscle pathology in dystrophin-deficient mice.Skeletal muscle · 2015Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Clinical application of potent anthracycline anticancer drugs, especially doxorubicin (DOX), is limited by a toxic cardiac side effect that is not fully understood and preventive strategies are yet to be established. Studies in genetically modified mice have demonstrated that focal adhesion kinase (FAK) plays a key role in regulating adaptive responses of the adult myocardium to pathological stimuli through activation of intracellular signaling cascades that facilitate cardiomyocyte growth and survival. The objective of this study was to determine if targeted myocardial FAK activation could protect the heart from DOX-induced de-compensation and to characterize the underlying mechanisms. To this end, mice with myocyte-restricted FAK knock-out (MFKO) or myocyte-specific expression of an active FAK variant (termed SuperFAK) were subjected to DOX treatment. FAK depletion enhanced susceptibility to DOX-induced myocyte apoptosis and cardiac dysfunction, while elevated FAK activity provided remarkable cardioprotection. Our mec6hanistic studies reveal a heretofore unappreciated role for the protective cyclin-dependent kinase inhibitor p21 in the repression of the pro-apoptotic BH3-only protein Bim and the maintenance of mitochondrial integrity and myocyte survival. DOX treatment induced proteasomal degradation of p21, which exacerbated mitochondrial dysfunction and cardiomyocyte apoptosis. FAK was both necessary and sufficient for maintaining p21 levels following DOX treatment and depletion of p21 compromised FAK-dependent protection from DOX. These findings identify p21 as a key determinant of DOX resistance downstream of FAK in cardiomyocytes and indicate that cardiac-restricted enhancement of the FAK/p21 signaling axis might be an effective strategy to preserve myocardial function in patients receiving anthracycline chemotherapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.