Recent clinical investigations indicate that anthracycline-based chemotherapies induce early declines in heart mass in cancer patients.

 

Abstract

Recent clinical investigations indicate that anthracycline-based chemotherapies induce early declines in heart mass in cancer patients.  Heart mass decline may be caused by a decrease in cardiac cell number due to increased cell death, or by a reduction in cell size due to atrophy. We previously reported that an anthracycline, doxorubicin (DOX), induces apoptotic death of cardiomyocytes by activating cyclin-dependent kinase 2 (CDK2). However, the signaling pathway downstream of CDK2 remains to be characterized, and it is also unclear whether the same pathway mediates cardiac atrophy. Here, we demonstrate that DOX exposure induces CDK2-dependent phosphorylation of the transcription factor forkhead box O1 (FOXO1) at Ser-249, leading to transcription of its pro-apoptotic target gene, Bcl-2-interacting mediator of cell death (Bim). In cultured cardiomyocytes, treatment with the FOXO1 inhibitor AS1842856 or transfection with FOXO1-specific siRNAs protected against DOX-induced apoptosis and mitochondrial damage. Oral administration of AS1842856 in mice abrogated apoptosis and prevented DOX-induced cardiac dysfunction. Intriguingly, the pharmacological FOXO1 inhibition also attenuated DOX-induced cardiac atrophy, likely due to repression of muscle RING finger 1 (MuRF1), a pro-atrophic FOXO1 target gene. In conclusion, DOX exposure induces CDK2-dependent FOXO1 activation, resulting in cardiomyocyte apoptosis and atrophy. Our results identify FOXO1 as a promising drug target for managing DOX-induced cardiotoxicity. We propose that FOXO1 inhibitors may have potential as cardioprotective therapeutics during cancer chemotherapy.

PMID: 32075913 [PubMed - as supplied by publisher]

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