title: Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21(Cip1.).
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.
authors.affiliation: Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Zhaokang
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: DiMichele
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.affiliation: Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Vaziri
authors.affiliation: Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Mack
authors.affiliation: Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: jmt3x@med.unc.edu.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Taylor
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C000606778:Bcl2l11 protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D004317:Doxorubicin; D051417:Focal Adhesion Kinase 1
keywords: Anthracycline cardiomyopathy; Apoptosis; CDK; CDKI; Cardiomyocyte; Cell cycle; DOX; FAK; MFKO; Mitochondria; NRCMs; NTG; SF; SF2; Super activatible FAK variant, or SuperFAK; cardiac-specific SF transgenic mice line 2; cyclin-dependent kinase; cyclin-dependent kinase inhibitor; doxorubicin; focal adhesion kinase; myocyte-restricted FAK knockout mice; neonatal rat cardiomyocytes; non-transgenic littermate control mice