Doxorubicin-induced apoptosis is exacerbated by MG53 and associated with altered Akt signaling in H9c2 cells

Chemotherapy drugs such as doxorubicin (DOX) are frequently used to treat cancer, but its negative impact on the heart reduces its effectiveness. Among the members of the TRIM protein family, mitsugumin (MG)53, also known as TRIM72, is unique. It is primarily present in the plasma membrane of cardiac and skeletal muscle cells and has been demonstrated to participate in mending cellular membrane damage while protecting against heart ischemia/reperfusion injury. This research investigated the role of MG53 in DOX-induced apoptosis using H9c2 cells, a cardiomyoblast cell line, as an experimental model. Our findings indicate that DOX treatment statistically significantly upregulates MG53 expression in H9c2 cells. Furthermore, MG53 overexpression exacerbated DOX-induced apoptosis, as confirmed by elevated levels of cleaved-caspase3 and BAX and reduced expression of Bcl-2. Flow cytometry analysis supported the elevated cell death rate in cells overexpressing MG53. Additionally, MG53 overexpression was associated with reduced phosphorylation levels of protein kinase B (AKT), as indicated by the decreased phosphorylation levels of AKT. Conversely, silencing MG53 through siRNA increased the phosphorylation levels of AKT. These results imply that MG53 exacerbates DOX-induced apoptosis, related to reduced AKT phosphorylation. Our investigation sheds light on the detrimental effects of MG53 in DOX-induced myocardial damage and underscores its potential as a therapeutic target for alleviating DOX treatment-related heart toxicity. SIGNIFICANCE STATEMENT: This study reveals that mitsugumin 53 exacerbates doxorubicin-induced apoptosis in H9c2 cells, associated with altered protein kinase B signaling. Targeting mitsugumin 53 may offer a novel therapeutic approach to mitigate doxorubicin-associated cardiotoxicity.