ArticleCell death & disease2016
Doxorubicin attenuates CHIP-guarded HSF1 nuclear translocation and protein stability to trigger IGF-IIR-dependent cardiomyocyte death.
Article in Cell death & disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 45 citations in OpenAlex.
- Bisphosphate nucleotidase 1 promotes progression and docetaxel resistance in triple-negative breast cancer via STUB1-mediated destabilization of LIMA1.Cell death & disease · 2026Article
- HSF1-DBC1 axis drives prostate cancer progression by activating a metastatic transcriptional program.Experimental & molecular medicine · 2025Article
- Sheng Mai San Mitigates Heat Stress-Induced Myocardial Injury by Coordinated Regulation of the Keap1-Nrf2-HO-1 and Stub1-HSF1 Signaling Pathways.Antioxidants (Basel, Switzerland) · 2025Article
- CHIP and aging: a key regulator of proteostasis and cellular senescence.Biogerontology · 2025Review
- Chaperone-assisted E3 ligase-engineered mesenchymal stem cells target hyperglycemia-induced p53 for ubiquitination and proteasomal degradation ameliorates self-renewal.Biological research · 2025Article
- HSF1 Activation Mechanisms, Disease Roles, and Small Molecule Therapeutics.International journal of biological sciences · 2025Review
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- Targeting HSF1 for cancer treatment: mechanisms and inhibitor development.Theranostics · 2023Review
- E3 ligase activity of Carboxyl terminus of Hsc70 interacting protein (CHIP) in Wharton's jelly derived mesenchymal stem cells improves their persistence under hyperglycemic stress and promotes the prophylactic effects against diabetic cardiac damages.Bioengineering & translational medicine · 2021Article
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- Cardiac Protective Effect of Kirenol against Doxorubicin-Induced Cardiac Hypertrophy in H9c2 Cells through Nrf2 Signaling via PI3K/AKT Pathways.International journal of molecular sciences · 2021Article
- Garcinol Attenuates Lipoprotein(a)-Induced Oxidative Stress and Inflammatory Cytokine Production in Ventricular Cardiomyocyte through α7-Nicotinic Acetylcholine Receptor-Mediated Inhibition of the p38 MAPK and NF-κB Signaling Pathways.Antioxidants (Basel, Switzerland) · 2021Article
- Conserved and Unique Roles of Chaperone-Dependent E3 Ubiquitin Ligase CHIP in Plants.Frontiers in plant science · 2021Review
- C-terminus of Hsp70 Interacting Protein (CHIP) and Neurodegeneration: Lessons from the Bench and Bedside.Current neuropharmacology · 2021Review
- Review
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- Synergistic cardiac pathological hypertrophy induced by high-salt diet in IGF-IIRα cardiac-specific transgenic rats.PloS one · 2019Article
- Rab9-dependent autophagy is required for the IGF-IIR triggering mitophagy to eliminate damaged mitochondria.Journal of cellular physiology · 2018Article
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Doxorubicin (DOX) is one of the most effective antitumor drugs, but its cardiotoxicity has been a major concern for its use in cancer therapy for decades. Although DOX-induced cardiotoxicity has been investigated, the underlying mechanisms responsible for this cardiotoxicity have not been completely elucidated. Here, we found that the insulin-like growth factor receptor II (IGF-IIR) apoptotic signaling pathway was responsible for DOX-induced cardiotoxicity via proteasome-mediated heat shock transcription factor 1 (HSF1) degradation. The carboxyl-terminus of Hsp70 interacting protein (CHIP) mediated HSF1 stability and nuclear translocation through direct interactions via its tetratricopeptide repeat domain to suppress IGF-IIR expression and membrane translocation under physiological conditions. However, DOX attenuated the HSF1 inhibition of IGF-IIR expression by diminishing the CHIP-HSF1 interaction, removing active nuclear HSF1 and triggering HSF1 proteasomal degradation. Overexpression of CHIP redistributed HSF1 into the nucleus, inhibiting IGF-IIR expression and preventing DOX-induced cardiomyocyte apoptosis. Moreover, HSF1A, a small molecular drug that enhances HSF1 activity, stabilized HSF1 expression and minimized DOX-induced cardiac damage in vitro and in vivo. Our results suggest that the cardiotoxic effects of DOX result from the prevention of CHIP-mediated HSF1 nuclear translocation and activation, which leads to an upregulation of the IGF-IIR apoptotic signaling pathway. We believe that the administration of an HSF1 activator or agonist may further protect against the DOX-induced cell death of cardiomyocytes.
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