Modulation of cardiac AKT and STAT3 signalling in preclinical cancer models and their impact on the heart.
Biochim Biophys Acta Mol Cell Res
; 1867(3): 118519, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-31374232
ABSTRACT
BACKGROUND:
Advanced cancer induces fundamental cardiac changes and promotes body wasting and heart failure. We evaluated the impact of cancer on major cardiac signalling pathways, and resulting consequences for the heart. METHODS ANDRESULTS:
Metastatic melanoma disease was induced in male C57BL/6â¯N mice by intraperitoneal injection of the melanoma cell line B16F10 and lead to cardiac atrophy and heart failure. Analyses of key cardiac signalling pathways in left ventricular tissue revealed increased activation of STAT3 and reduced activation of AKT, p38 and ERK1/2. Markers of the ubiquitin proteasomal system (UPS Atrogin-1) and of mitophagy/autophagy (LC3b, BNIP3) were upregulated. Tumour-bearing C57BL/6â¯N mice with a cardiomyocyte-specific overexpression of a constitutively active AKT transgene (AKTtg) displayed less cardiac atrophy and dysfunction and normalized Atrogin-1, LC3b and BNIP3 expression while the cardiomyocyte-specific knockout of STAT3 (CKO) had no major effect on these parameters compared to WT.CONCLUSION:
Cancer alters major cardiac signalling pathways and subsequently the UPS, mitophagy and autophagy. The present study suggests that cancer-induced reduction of cardiomyocyte AKT contributes to these alterations as they were attenuated in tumour-bearing AKTtg mice. In turn, increased cardiomyocyte STAT3 activation appears less relevant, as tumour-induced impairment on the heart was largely similar in CKO and WT mice. Since oncologic therapies frequently target AKT and/or STAT3, their impact on the heart might be different in tumour-bearing mice compared to healthy mice, a feature suggesting to test tumour therapies also in tumour disease models and not only under healthy conditions. This article is part of a Special Issue entitled Cardiomyocyte biology new pathways of differentiation and regeneration edited by Marijke Brink, Marcus C. Schaub, and Christian Zuppinger.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Melanoma Experimental
/
Proteínas Proto-Oncogênicas c-akt
/
Fator de Transcrição STAT3
/
Coração
/
Insuficiência Cardíaca
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Biochim Biophys Acta Mol Cell Res
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Alemanha