1. Academic Validation
  2. Doxorubicin induces cardiomyocyte apoptosis and atrophy through cyclin-dependent kinase 2-mediated activation of forkhead box O1

Doxorubicin induces cardiomyocyte apoptosis and atrophy through cyclin-dependent kinase 2-mediated activation of forkhead box O1

  • J Biol Chem. 2020 Mar 27;295(13):4265-4276. doi: 10.1074/jbc.RA119.011571.
Peng Xia 1 Jingrui Chen 1 Yuening Liu 1 Maya Fletcher 2 Brian C Jensen 3 Zhaokang Cheng 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington 99202-2131.
  • 2 Department of Biology, Gonzaga University, Spokane, Washington 99258.
  • 3 Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7075.
  • 4 Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington 99202-2131. Electronic address: [email protected].
Abstract

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.

Keywords

Adriamycin; anticancer drug; cardiac muscle; cardiomyopathy; cardiovascular disease; cell cycle; heart failure.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-100596
    99.83%, Foxo1 Inhibitor