Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
Biochim Biophys Acta Mol Cell Res. 2020 Mar;1867(3):118519. doi: 10.1016/j.bbamcr.2019.07.014. Epub 2019 Jul 31.
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.
Metastatic melanoma disease was induced in male C57BL/6 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/6 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.
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.
晚期癌症会引起心脏的根本性变化，并导致身体消瘦和心力衰竭。我们评估了癌症对主要心脏信号通路的影响，以及对心脏的相应后果。
通过向 C57BL/6N 雄性小鼠腹腔内注射黑色素瘤细胞系 B16F10 诱导转移性黑色素瘤疾病，导致心脏萎缩和心力衰竭。对左心室组织中关键心脏信号通路的分析显示，STAT3 的激活增加，而 AKT、p38 和 ERK1/2 的激活减少。泛素蛋白酶体系统 (UPS：Atrogin-1) 和自噬/噬溶酶体 (LC3b、BNIP3) 的标志物上调。与 WT 相比，具有心肌细胞特异性过表达组成型激活 AKT 转基因 (AKTtg) 的荷瘤 C57BL/6N 小鼠的心脏萎缩和功能障碍较少，Atrogin-1、LC3b 和 BNIP3 的表达正常化，而心肌细胞特异性敲除 STAT3 (CKO) 对这些参数没有重大影响。
癌症改变了主要的心脏信号通路，随后改变了 UPS、自噬和溶酶体。本研究表明，癌症诱导的心肌细胞 AKT 减少导致了这些变化，因为在荷瘤 AKTtg 小鼠中这些变化得到了减弱。相反，增加心肌细胞 STAT3 的激活似乎不太相关，因为肿瘤诱导的心脏损伤在 CKO 和 WT 小鼠中基本相似。由于肿瘤治疗通常靶向 AKT 和/或 STAT3，它们对心脏的影响在荷瘤小鼠中可能与健康小鼠不同，这一特征表明在肿瘤疾病模型中而不仅仅是在健康条件下测试肿瘤治疗方法。本文是由 Marijke Brink、Marcus C. Schaub 和 Christian Zuppinger 编辑的特刊“心肌细胞生物学：新的分化和再生途径”的一部分。
