Abstract
With the rapid increase of cancer survivors due to improved diagnosis and therapy in the past decades, cancer treatment-related cardiotoxicity is becoming an urgent concern for modern society. The anthracycline doxorubicin (DOX), one of the most effective chemotherapeutic agents to date, is known to cause cardiomyopathy through induction of cardiomyocyte apoptosis. We previously showed that the cyclin-dependent kinase (CDK) inhibitor p21 promotes resistance against DOX-induced apoptosis. In this study, we demonstrated that CDK2 activity and expression were significantly increased following DOX exposure in mouse heart and cultured neonatal rat cardiomyocytes (NRCMs). DOX-induced apoptosis, as measured by cleavage of caspase 3 and PARP, TUNEL staining, and MTT assay, was significantly suppressed by inhibition of CDK2 activity using small-molecule inhibitors, or CDK2-specific siRNA. Conversely, overexpression of CDK2 augmented DOX-induced apoptosis. DOX injection-induced CDK2 activation in mouse heart was correlated with upregulation of the BH3-only protein Bim. Mechanistically, CDK2 mediated DOX-induced expression of Bim, which was essential in triggering Bax/Bak-dependent mitochondrial outer membrane permeabilization. Pharmacological inhibition of CDK2 robustly repressed DOX-induced mitochondrial depolarization. These findings identify CDK2 as a key determinant of DOX-induced apoptosis in cardiomyocytes. Activation of CDK2 is necessary for DOX-induced Bim expression and mitochondrial damage. Also, pharmacological inhibition of CDK2 might be an effective cardioprotective strategy against anthracycline cardiotoxicity.
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