Inhibition of AMPK signalling by doxorubicin: at the crossroads of the cardiac responses to energetic, oxidative, and genotoxic stress.

Abstract

AIMS:

Cardiotoxic side effects of anthracyclines, the most widely used anticancer drugs, are well documented, while mechanisms involved are not fully elucidated. The cellular energy sensor and regulator AMP-activated protein kinase (AMPK) was suggested as a putative mediator of cardiotoxicity of doxorubicin, the leading anthracycline drug, by our earlier work. Here, we study the interference of doxorubicin with AMPK signalling and potentially involved mechanisms.

METHODS AND RESULTS:

Effects of doxorubicin on cell signalling are studied in isolated Langendorff-perfused Wistar rat hearts and in hearts from doxorubicin-treated Wistar rats. In both models, doxorubicin induces energetic, oxidative, and genotoxic stress. Despite energy depletion and unaffected AMPK upstream signalling, doxorubicin does not activate the AMPK pathway and even reduces basal phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase. In contrast, oxidative and genotoxic stress do activate pro-survival mitogen-activated protein kinase (MAPK) and Akt pathways, the latter via DNA-dependent protein kinase activation triggered by DNA damage. Combined inhibition of AMPK and activation of Akt and MAPK lead to activation of growth-stimulating mammalian target of rapamycin (mTOR) signalling.

CONCLUSION:

Our results suggest that in the doxorubicin-challenged heart, a combined energetic, oxidative, and genotoxic stress elicits a specific, hierarchical response where AMPK is inhibited at least partially by the known negative cross-talk with Akt and MAPK pathways, largely triggered by DNA damage signalling. Although such signalling can be protective, e.g. by limiting apoptosis, it primarily induces a negative feedback that increases cellular energy deficits, and via activation of mTOR signalling, it also contributes to the pathological cardiac phenotype in chronic doxorubicin toxicity.

• Authors: Séverine Gratia, Laurence Kay, Lucia Potenza, Amal Seffouh, Valérie Novel-Chaté, Coralie Schnebelen, Piero Sestili, Uwe Schlattner, Malgorzata Tokarska-Schlattner
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 95 Issue 3 Pg. 290-9 (Aug 01 2012) ISSN: 1755-3245 [Electronic] England
• PMID: 22461523 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Protein Kinase Inhibitors
• Doxorubicin
• mTOR protein, rat
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases
• AMP-Activated Protein Kinases
• Acetyl-CoA Carboxylase

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Acetyl-CoA Carboxylase (metabolism)
• Animals
• Antibiotics, Antineoplastic (toxicity)
• DNA Damage
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Doxorubicin (toxicity)
• Energy Metabolism (drug effects)
• Enzyme Activation
• Heart Diseases (chemically induced, enzymology, genetics, pathology, physiopathology)
• Male
• Mitogen-Activated Protein Kinases (metabolism)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Oxidative Stress (drug effects)
• Phosphorylation
• Protein Kinase Inhibitors (toxicity)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Time Factors