Doxorubicin attenuates CHIP-guarded HSF1 nuclear translocation and protein stability to trigger IGF-IIR-dependent cardiomyocyte death.
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.
Translation Research Core, China Medical University Hospital, China Medical University, Taichung, Taiwan.
Chih-Yang
CY
Huang
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
Wei-Wen
WW
Kuo
Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
Jeng-Fan
JF
Lo
Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, Taiwan.
Tsung-Jung
TJ
Ho
Division of Cardiology, China Medical University Hospital, Taichung, Taiwan.
Pei-Ying
PY
Pai
Cancer Center, China Medical University Hospital, Taichung, Taiwan.
Shu-Fen
SF
Chiang
Department of Pathology, China Medical University Hospital, Taichung, Taiwan.
Pei-Yu
PY
Chen
Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin, Taiwan.
Fu-Jen
FJ
Tsai
Department of Healthcare Administration, Asia University, Taichung, Taiwan.
Chang-Hai
CH
Tsai
Chinese Medicine Department, China Medical University Beigang Hospital, Yunlin, Taiwan.|Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
Chih-Yang
CY
Huang
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D054715:Cardiotoxins / Q000633:toxicity; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D000076249:Heat Shock Transcription Factors; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D017208:Rats, Wistar; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D054715:Cardiotoxins; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D017527:Receptor, IGF Type 2; D014157:Transcription Factors; D004317:Doxorubicin; D046988:Proteasome Endopeptidase Complex