Gene interactions and pathways from curated databases and text-mining
Cardiovasc Res 2012, PMID: 22461523

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

Gratia, Séverine; Kay, Laurence; Potenza, Lucia; Seffouh, Amal; Novel-Chaté, Valérie; Schnebelen, Coralie; Sestili, Piero; Schlattner, Uwe; Tokarska-Schlattner, Malgorzata

OBJECTIVE

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.

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.

CONCLUSIONS

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.

Diseases/Pathways annotated by Medline MESH: Disease Models, Animal, Heart Diseases
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Text Mining Data

mammalian target of rapamycin (mTOR) ⊣ MAPK: " Combined inhibition of AMPK and activation of Akt and MAPK lead to activation of growth stimulating mammalian target of rapamycin (mTOR) signalling "

mammalian target of rapamycin (mTOR) ⊣ Akt: " Combined inhibition of AMPK and activation of Akt and MAPK lead to activation of growth stimulating mammalian target of rapamycin (mTOR) signalling "

mammalian target of rapamycin (mTOR) ⊣ AMPK: " Combined inhibition of AMPK and activation of Akt and MAPK lead to activation of growth stimulating mammalian target of rapamycin (mTOR) signalling "

Manually curated Databases

No curated data.