Doxorubicin attenuates CHIP-guarded HSF1 nuclear translocation and protein stability to trigger IGF-IIR-dependent cardiomyocyte death
Chih-Yang Huang1, Wei-Wen Kuo2, Jeng-Fan Lo3
1Translation Research Core, China Medical University Hospital, China Medical University, Taichung, Taiwan.
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.
Insights
Doxorubicin (DOX) causes heart damage by degrading heat shock transcription factor 1 (HSF1), a process involving the insulin-like growth factor receptor II (IGF-IIR) pathway. Enhancing HSF1 activity may protect against this cardiotoxicity.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Doxorubicin (DOX) is a potent anticancer drug with significant cardiotoxicity.
- The precise molecular mechanisms underlying DOX-induced cardiotoxicity remain incompletely understood.
- Insulin-like growth factor receptor II (IGF-IIR) is implicated in cellular apoptosis.
Purpose of the Study:
- To elucidate the mechanisms of DOX-induced cardiotoxicity.
- To investigate the role of heat shock transcription factor 1 (HSF1) and its interacting proteins in DOX cardiotoxicity.
- To explore potential therapeutic strategies targeting HSF1.
Main Methods:
- Investigated the interaction between carboxyl-terminus of Hsp70 interacting protein (CHIP) and HSF1.
- Examined the effect of DOX on HSF1 stability, nuclear translocation, and proteasomal degradation.
- Assessed the impact of CHIP overexpression and HSF1 activation (using HSF1A) on DOX-induced cardiomyocyte apoptosis in vitro and in vivo.
Main Results:
- DOX induces cardiotoxicity by promoting proteasome-mediated degradation of HSF1.
- CHIP normally stabilizes HSF1, suppressing IGF-IIR expression and preventing apoptosis.
- DOX disrupts the CHIP-HSF1 interaction, leading to HSF1 degradation and IGF-IIR pathway activation.
- CHIP overexpression and HSF1A treatment protected cardiomyocytes from DOX-induced apoptosis and cardiac damage.
Conclusions:
- DOX cardiotoxicity arises from impaired CHIP-mediated HSF1 nuclear translocation and activation, upregulating the IGF-IIR apoptotic pathway.
- Targeting HSF1 with activators or agonists presents a promising therapeutic approach to mitigate DOX-induced cardiotoxicity.
- Understanding the CHIP-HSF1-IGF-IIR axis offers new insights into preventing chemotherapy-related heart damage.
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