NDLI: ERKs/p53 signal transduction pathway is involved in doxorubicin-induced apoptosis in H9c2 cells and cardiomyocytes.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Liu, Jiahao Mao, Weike Ding, Bo Liang, Chang-seng
Description	Country affiliation: United States Author Affiliation: Liu J ( Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.)
Abstract	The cardiotoxic effects of doxorubicin, a potent chemotherapeutic agent, have been linked to DNA damage, oxidative mitochondrial damage, and nuclear translocation of p53, but the exact molecular mechanisms causing p53 transactivation and doxorubicin-induced cardiomyopathy are not clear. The present study was carried out to determine whether extracellular signal-regulated kinases (ERKs), which are known to be activated by DNA damaging agents, are responsible for doxorubicin-induced p53 activation and oxidative mitochondrial damage in H9c2 cells. Cell death was measured by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, annexin V-fluorescein isothiocyanate, activation of caspase-9 and -3, and cleavage of poly(ADP-ribose) polymerase (PARP). We found that doxorubicin produced cell death in H9c2 cells in a time-dependent manner, beginning at 6 h, and these changes are associated decreased expression of Bcl-2, increases in Bax and p53 upregulated modulator of apoptosis-alpha expression, and collapse of mitochondria membrane potential. The changes in cell death and Bcl-2 family proteins, however, were preceded by earlier activation and nuclear translocation of ERKs, followed by increased phosphorylation at Ser15 and nuclear translocation of the phosphorylated p53. The functional importance of ERK1/2 and p53 in doxorubicin-induced toxicity was further demonstrated by the specific ERK inhibitor U-0126 and p53 inhibitor pifithrin (PFT)-alpha, which abrogated the changes in Bcl-2 family proteins and cell death produced by doxorubicin. U-0126 blocked the phosphorylation and nuclear translocation of both ERK1/2 and p53, whereas PFT-alpha blocked only the changes in p53. Doxorubicin and ERK inhibitors produced similar changes in ERK1/2-p53, PARP, and caspase-3 in neonatal rat cultured cardiomyocytes. Thus we conclude that ERK1/2 are functionally linked to p53 and that the ERK1/2-p53 cascade is the upstream signaling pathway responsible for doxorubicin-induced cardiac cell apoptosis. ERKs and p53 may be considered as novel therapeutic targets for the treatment of doxorubicin-induced cardiotoxicity.
File Format	HTM / HTML
ISSN	03636135
e-ISSN	15221539
DOI	10.1152/ajpheart.00407.2008
Journal	AJP: Heart and Circulatory Physiology
Issue Number	5
Volume Number	295
Language	English
Publisher	American Physiological Society
Publisher Date	2008-11-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Physiology Discipline Cardiology Antibiotics, Antineoplastic Toxicity Apoptosis Drug Effects Doxorubicin Mitogen-activated Protein Kinase 1 Metabolism Mitogen-activated Protein Kinase 3 Myocytes, Cardiac Signal Transduction Tumor Suppressor Protein P53 Active Transport, Cell Nucleus Animals Animals, Newborn Benzothiazoles Pharmacology Butadienes Caspases Cells, Cultured Membrane Potential, Mitochondrial Antagonists & Inhibitors Enzymology Pathology Nitriles Phosphorylation Poly(adp-ribose) Polymerases Protein Kinase Inhibitors Proto-oncogene Proteins C-bcl-2 Rats, Sprague-dawley Time Factors Toluene Analogs & Derivatives Bcl-2-associated X Protein Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Cardiology and Cardiovascular Medicine

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