title: Doxorubicin induces protein ubiquitination and inhibits proteasome activity during cardiotoxicity.
abstract: Anthracycline-induced cardiotoxicity is a clinically complex syndrome that leads to substantial morbidity and mortality for cancer survivors. Despite several years of research, the underlying molecular mechanisms remain largely undefined and thus effective therapies to manage this condition are currently non-existent. This study therefore aimed to determine the contribution of the ubiquitin-proteasome pathway (UPP) and endoplasmic reticulum (ER)-stress within this context. Cardiotoxicity was induced with the use of doxorubicin (DXR) in H9C2 rat cardiomyoblasts (3 μM) for 24 h, whereas the tumour-bearing GFP-LC3 mouse model was treated with a cumulative dose of 20 mg/kg. Markers for proteasome-specific protein degradation were significantly upregulated in both models following DXR treatment, however proteasome activity was lost. Moreover, ER-stress as assessed by increased ER load was considerably augmented (in vitro) with modest binding of DXR with ER. These results suggest that DXR induces intrinsic activation of the UPP and ER stress which ultimately contributes to dysfunction of the myocardium during this phenomenon.
authors: Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa. bsishi@sun.ac.za
authors: Balindiwe J N
authors: BJ
authors: Sishi
authors: Benjamin
authors: B
authors: Loos
authors: Jacques
authors: J
authors: van Rooyen
authors: Anna-Mart
authors: AM
authors: Engelbrecht
mesh_terms: D000818:Animals; D054715:Cardiotoxins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects* / Q000502:physiology; D005260:Female; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D054875:Ubiquitination / Q000187:drug effects* / Q000502:physiology
chemical_list: D054715:Cardiotoxins; D061988:Proteasome Inhibitors; D004317:Doxorubicin; D046988:Proteasome Endopeptidase Complex