Abstract
With the rapid increase in cancer survival because of improved diagnosis and therapy in the past decades, cancer treatment-related cardiotoxicity is becoming an urgent healthcare concern. The anthracycline doxorubicin (DOX), one of the most effective chemotherapeutic agents to date, causes cardiomyopathy by inducing cardiomyocyte apoptosis. We demonstrated previously that overexpression of the cyclin-dependent kinase (CDK) inhibitor p21 promotes resistance against DOX-induced cardiomyocyte apoptosis. Here we show that DOX exposure provokes cardiac CDK2 activation and cardiomyocyte cell cycle S phase reentry, resulting in enhanced cellular sensitivity to DOX. Genetic or pharmacological inhibition of CDK2 markedly suppressed DOX-induced cardiomyocyte apoptosis. Conversely, CDK2 overexpression augmented DOX-induced apoptosis. We also found that DOX-induced CDK2 activation in the mouse heart is associated with up-regulation of the pro-apoptotic BCL2 family member BCL2-like 11 (Bim), a BH3-only protein essential for triggering Bax/Bak-dependent mitochondrial outer membrane permeabilization. Further experiments revealed that DOX induces cardiomyocyte apoptosis through CDK2-dependent expression of Bim. Inhibition of CDK2 with roscovitine robustly repressed DOX-induced mitochondrial depolarization. In a cardiotoxicity model of chronic DOX exposure (5 mg/kg weekly for 4 weeks), roscovitine administration significantly attenuated DOX-induced contractile dysfunction and ventricular remodeling. These findings identify CDK2 as a key determinant of DOX-induced cardiotoxicity. CDK2 activation is necessary for DOX-induced Bim expression and mitochondrial damage. Our results suggest that pharmacological inhibition of CDK2 may be a cardioprotective strategy for preventing anthracycline-induced heart damage.
Highlights
With the rapid increase in cancer survival because of improved diagnosis and therapy in the past decades, cancer treatment–related cardiotoxicity is becoming an urgent healthcare concern
We explored the role of CDK2 in DOX-induced cardiac toxicity and demonstrated that DOX exposure induced cardiomyocyte apoptosis and cardiomyopathy through activation of CDK2
We previously demonstrated that DOX-induced cardiomyocyte apoptosis was suppressed by the Cip/Kip family cyclin-dependent kinase (CDK) inhibitor p21 [7], which mediates G1/S cell cycle arrest primarily by inhibiting the kinase activity of CDK2 [8]
Summary
We previously demonstrated that DOX-induced cardiomyocyte apoptosis was suppressed by the Cip/Kip family CDK inhibitor p21 [7], which mediates G1/S cell cycle arrest primarily by inhibiting the kinase activity of CDK2 [8]. To determine whether activation of CDK2 would augment DOX-induced apoptosis, NRCMs were transfected with plasmids expressing p33 or p39 CDK2 prior to treatment with DOX for 8 h Overexpression of both isoforms of CDK2 significantly enhanced DOX-induced PARP cleavage (Fig. 4A). Pharmacologic inhibition of CDK2 activity with roscovitine significantly reduced the Bim protein level following DOX treatment (Fig. 6F), further supporting a critical role of CDK2 activation in DOX-induced expression of the pro-apoptotic protein Bim. drial depolarization, calculated as the ratio of green to red fluorescence intensity, was robustly induced by DOX stimulation (Fig. 7). Pretreatment with roscovitine markedly suppressed DOX-induced mitochondrial depolarization (Fig. 7), suggesting that pharmacologic inhibition of CDK2 preserved mitochondrial integrity in response to DOX treatment, likely by repressing Bim expression. Administration of the CDK inhibitor roscovitine alleviated DOX-induced cardiac dysfunction and ventricular remodeling
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