Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 13, Pages 4265-4276Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.011571
Keywords
anticancer drug; cardiovascular disease; cardiomyopathy; heart failure; cardiac muscle; cell cycle; Adriamycin
Categories
Funding
- NHLBI, National Institutes of Health [R00HL119605, R56HL145034, RO1HL140067]
- ASPET Summer Undergraduate Research Program
- Washington State University College of Pharmacy and Pharmaceutical Sciences
Ask authors/readers for more resources
Recent clinical investigations indicate that anthracycline-based chemotherapies induce early decline in heart mass in cancer patients. Heart mass decline may be caused by a decrease in cardiac cell number because of increased cell death or by a reduction in cell size because of 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 proapoptotic 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, pharmacological FOXO1 inhibition also attenuated DOX-induced cardiac atrophy, likely because of repression of muscle RING finger 1 (MuRF1), a proatrophic 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 therapeutic agents during cancer chemotherapy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available