ArticleThe Journal of biological chemistry2014
AMP-activated protein kinase α2 and E2F1 transcription factor mediate doxorubicin-induced cytotoxicity by forming a positive signal loop in mouse embryonic fibroblasts and non-carcinoma cells.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- A Systematic Review of the Potential Chemoprotective Effects of Resveratrol on Doxorubicin-Induced Cardiotoxicity: Focus on the Antioxidant, Antiapoptotic, and Anti-Inflammatory Activities.Oxidative medicine and cellular longevity · 2021Pooled it
- Pleiotropic role of CCR9/CCL25 signaling in adriamycin-induced cardiomyopathy.Journal of advanced research · 2025Article
- The E2F family: a ray of dawn in cardiomyopathy.Molecular and cellular biochemistry · 2025Review
- Doxorubicin or Epirubicin Versus Liposomal Doxorubicin Therapy-Differences in Cardiotoxicity.Cardiovascular toxicology · 2025Review
- Purple Corn Extract Prevents Doxo-Induced Cardiotoxicity by Counteracting AMPK Activation and p53 Acetylation in HL-1 and Primary Cardiomyocytes.Oxidative medicine and cellular longevity · 2025Article
- Potential Roles of Melatonin in Doxorubicin-Induced Cardiotoxicity: From Cellular Mechanisms to Clinical Application.Pharmaceutics · 2023Review
- Mitochondrial micropeptide STMP1 promotes G1/S transition by enhancing mitochondrial complex IV activity.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Molecular insights into the pathophysiology of doxorubicin-induced cardiotoxicity: a graphical representation.Archives of toxicology · 2022Review
- In Vitro and In Vivo Cardioprotective Effects of Curcumin against Doxorubicin-Induced Cardiotoxicity: A Systematic Review.Journal of oncology · 2022Review
- Melatonin and doxorubicin synergistically enhance apoptosis via autophagy-dependent reduction of AMPKα1 transcription in human breast cancer cells.Experimental & molecular medicine · 2021Article
- Stem cell-derived exosomes repair ischemic muscle injury by inhibiting the tumor suppressor Rb1-mediated NLRP3 inflammasome pathway.Signal transduction and targeted therapy · 2021Article
- Synergistic antitumor effect of resveratrol and sorafenib on hepatocellular carcinoma through PKA/AMPK/eEF2K pathway.Food & nutrition research · 2021Article
- TOM40 Inhibits Ovarian Cancer Cell Growth by Modulating Mitochondrial Function Including Intracellular ATP and ROS Levels.Cancers · 2020Article
- The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity.Cardiovascular drugs and therapy · 2020Review
- The miRNA-449 family mediates doxorubicin resistance in triple-negative breast cancer by regulating cell cycle factors.Scientific reports · 2019Article
- SETDB1 mediated FosB expression increases the cell proliferation rate during anticancer drug therapy.BMB reports · 2016Article
- AMP-Activated Protein Kinase Directly Phosphorylates and Destabilizes Hedgehog Pathway Transcription Factor GLI1 in Medulloblastoma.Cell reports · 2015Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Doxorubicin is one of the most widely used anti-cancer drugs, but its clinical application is compromised by severe adverse effects in different organs including cardiotoxicity. In the present study we explored mechanisms of doxorubicin-induced cytotoxicity by revealing a novel role for the AMP-activated protein kinase α2 (AMPKα2) in mouse embryonic fibroblasts (MEFs). Doxorubicin robustly induced the expression of AMPKα2 in MEFs but slightly reduced AMPKα1 expression. Our data support the previous notion that AMPKα1 harbors survival properties under doxorubicin treatment. In contrast, analyses of Ampkα2(-/-) MEFs, gene knockdown of AMPKα2 by shRNA, and inhibition of AMPKα2 activity with an AMPK inhibitor indicated that AMPKα2 functions as a pro-apoptotic molecule under doxorubicin treatment. Doxorubicin induced AMPKα2 at the transcription level via E2F1, a transcription factor that regulates apoptosis in response to DNA damage. E2F1 directly transactivated the Ampkα2 gene promoter. In turn, AMPKα2 significantly contributed to stabilization and activation of E2F1 by doxorubicin, forming a positive signal amplification loop. AMPKα2 directly interacted with and phosphorylated E2F1. This signal loop was also detected in H9c2, C2C12, and ECV (human epithelial cells) cells as well as mouse liver under doxorubicin treatment. Resveratrol, which has been suggested to attenuate doxorubicin-induced cytotoxicity, significantly blocked induction of AMPKα2 and E2F1 by doxorubicin, leading to protection of these cells. This signal loop appears to be non-carcinoma-specific because AMPKα2 was not induced by doxorubicin in five different tested cancer cell lines. These results suggest that AMPKα2 may serve as a novel target for alleviating the cytotoxicity of doxorubicin.
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