Huang Chih-Yang, Kuo Wei-Wen, Lo Jeng-Fan, Ho Tsung-Jung, Pai Pei-Ying, Chiang Shu-Fen, Chen Pei-Yu, Tsai Fu-Jen, Tsai Chang-Hai, Huang Chih-Yang
Translation Research Core, China Medical University Hospital, China Medical University, Taichung, Taiwan.
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
Cell Death Dis. 2016 Nov 3;7(11):e2455. doi: 10.1038/cddis.2016.356.
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.
阿霉素（DOX）是最有效的抗肿瘤药物之一，但几十年来其心脏毒性一直是癌症治疗中使用该药物的主要担忧。尽管已经对DOX诱导的心脏毒性进行了研究，但其心脏毒性的潜在机制尚未完全阐明。在这里，我们发现胰岛素样生长因子受体II（IGF-IIR）凋亡信号通路通过蛋白酶体介导的热休克转录因子1（HSF1）降解导致DOX诱导的心脏毒性。在生理条件下，热休克蛋白70相互作用蛋白（CHIP）的羧基末端通过其四肽重复结构域直接相互作用介导HSF1的稳定性和核转位，以抑制IGF-IIR的表达和膜转位。然而，DOX通过减少CHIP-HSF1相互作用、去除活性核HSF1并触发HSF1蛋白酶体降解，减弱了HSF1对IGF-IIR表达的抑制作用。CHIP的过表达将HSF1重新分布到细胞核中，抑制IGF-IIR的表达并防止DOX诱导的心肌细胞凋亡。此外，小分子药物HSF1A可增强HSF1活性，在体外和体内稳定HSF1表达并使DOX诱导的心脏损伤最小化。我们的结果表明，DOX的心脏毒性作用是由于CHIP介导的HSF1核转位和激活受到抑制，从而导致IGF-IIR凋亡信号通路上调。我们认为，给予HSF1激活剂或激动剂可能进一步预防DOX诱导的心肌细胞死亡。
