Final Report Summary - ANTHRAPLUS (Doxorubicin-induced impairment of metabolic and stress signaling: A culprit of cardiotoxic action of the drug?)
Anthracyclines, in particular doxorubicin, are the most effective anticancer drugs. However, their serious side effect is a cardiotoxicity, which is not entirely understood.
In this project we have addressed doxorubicin-induced changes in cell signalling (mainly energy-related signalling) as a novel potential mediator of doxorubicin cardiotoxicity. Our approach was two-fold:
1. non-biased phosphoproteomic approach aiming at the identification of new phosphorylation events mediating response to doxorubicin
2. a targeted approach focusing on pathways identified by our previous studies, as signalling by LKB1, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Akt and mitogen-activated protein kinases (MAPK).
We have used two doxorubicin cardiotoxicity models: Langendorff perfused rat heart and an in vivo treated rat. The phosphoproteomic approach identified 22 proteins with a significantly changed phosphorylation status. Identified proteins were mainly involved in energy metabolism (e.g. pyruvate dehydrogenase and acyl-CoA dehydrogenase), sarcomere structure and function (e.g. desmin) or chaperone-like activities (e.g. alpha-crystallin B chain and prohibitin). These changes might be relevant for main symptoms of cardiac dysfunction related to doxorubicin treatment, namely energy imbalance and myofibrillar disorganisation. Using targeted analysis we have shown that in the doxorubicin-challenged heart, a combined energetic, oxidative, and genotoxic stress elicits a specific, hierarchical response where the key cellular energy sensor and regulator, AMPK, is inhibited at least partially by the known negative cross-talk with Akt and MAPK pathways. Such response is largely triggered by deoxyribonucleic acid (DNA) damage signalling. Protective effects of creatine and phosphocreatine were demonstrated and potential contributing mechanisms were suggested.
In this project we have addressed doxorubicin-induced changes in cell signalling (mainly energy-related signalling) as a novel potential mediator of doxorubicin cardiotoxicity. Our approach was two-fold:
1. non-biased phosphoproteomic approach aiming at the identification of new phosphorylation events mediating response to doxorubicin
2. a targeted approach focusing on pathways identified by our previous studies, as signalling by LKB1, AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Akt and mitogen-activated protein kinases (MAPK).
We have used two doxorubicin cardiotoxicity models: Langendorff perfused rat heart and an in vivo treated rat. The phosphoproteomic approach identified 22 proteins with a significantly changed phosphorylation status. Identified proteins were mainly involved in energy metabolism (e.g. pyruvate dehydrogenase and acyl-CoA dehydrogenase), sarcomere structure and function (e.g. desmin) or chaperone-like activities (e.g. alpha-crystallin B chain and prohibitin). These changes might be relevant for main symptoms of cardiac dysfunction related to doxorubicin treatment, namely energy imbalance and myofibrillar disorganisation. Using targeted analysis we have shown that in the doxorubicin-challenged heart, a combined energetic, oxidative, and genotoxic stress elicits a specific, hierarchical response where the key cellular energy sensor and regulator, AMPK, is inhibited at least partially by the known negative cross-talk with Akt and MAPK pathways. Such response is largely triggered by deoxyribonucleic acid (DNA) damage signalling. Protective effects of creatine and phosphocreatine were demonstrated and potential contributing mechanisms were suggested.