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.
Highlights
Cardiotoxicity occurs frequently in patients with tumors treated with anthracyclines, such as doxorubicin (DOX)
Our previous findings clearly indicate that the IGF-II/ insulin-like growth factor receptor II (IGF-IIR) signaling pathway is implicated in the stages of progressive of heart failure, such as pathological hypertrophy,[10,11] myocardial remodeling fibrosis[5] and cardiomyocyte apoptosis.[12,13]
Our previous studies have demonstrated that activated membrane-bound IGF-IIR recruits Gαq to induce caspase-3-dependent apoptosis in response to injuries leading to the progression of heart failure, such as spontaneous hypertension-induced and abdominal aorta ligation-induced cardiac injury.[14,16]
Summary
Cardiotoxicity occurs frequently in patients with tumors treated with anthracyclines, such as doxorubicin (DOX). The cardiotoxicity of DOX involves increased oxidative stress, apoptosis and a direct effect on DNA synthesis in cardiomyocytes;[1,2,3] the detailed mechanism of DOX-induced heart failure is not well established. The co-chaperone carboxyl-terminus of Hsp[70] interacting protein (CHIP) possesses a tetratricopeptide repeat (TPR) domain at its N terminus for interactions with Hsp[70] and a U-box domain at its C terminus for ubiquitination.[21] CHIP has been shown to have a protective role by targeting misfolded or damaged proteins that are associated with the pathologies of neurodegenerative[21,22] and heart diseases.[23,24,25] CHIP can directly interact with the N-terminal domain of HSF1, facilitating HSF1 nuclear translocation and activation to protect against stress-induced apoptosis.[26,27] CHIP and HSF1 have been shown to be responsible for oxidative stress-induced cell death in neurons and cardiomyocytes,[28,29] the detailed mechanism of how CHIP protects cells from DOX-induced oxidative stress has not been well elucidated
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