Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
Department of Pathology, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated Guangren Hospital, Xi'an Jiaotong University Health Science Center, 21 Jiefang Road, Xi'an, 710005, Shaanxi, China.
Theranostics. 2023 Jan 1;13(2):560-577. doi: 10.7150/thno.79227. eCollection 2023.
Chemotherapy is a common clinical strategy for cancer treatment. However, the accompanied cardiomyopathy renders cancer patients under risk of another life-threatening condition. Whereas Hippo pathway is known to play key roles in both cancerogenesis and heart disease, it remains unclear whether Hippo pathway activation mediates chemotherapy-induced cardiomyopathy. In human breast cancer cells, doxorubicin (DOX) significantly induced upregulation of Hippo kinase Mst1, inhibitory phosphorylation of YAP, mitochondrial damage, reduced cell viability and increased apoptosis. Hippo pathway inactivation by Mst1-siRNA transfection effectively improved cell survival and mitigated mitochondrial damage and cell apoptosis. Another anti-cancer drug YAP inhibitor verteporfin also induced lower cancer cell viability, apoptosis and mitochondrial injury. Chronic treatment with DOX (4 mg/kg/week for 6 weeks) caused mitochondrial damage and dysfunction, oxidative stress and cardiac fibrosis, while acute DOX treatment (16 mg/kg single bolus) also induced myocardial oxidative stress and mitochondrial abnormalities. Chronic treatment with verteporfin (2 months) resulted in cardiomyopathy phenotypes comparable to that by chronic DOX regimen. In transgenic mice with cardiac overexpression of kinase-dead mutant Mst1 gene, these adverse cardiac effects of DOX were significantly attenuated relative to wild-type littermates. Anti-cancer action of both DOX and verteporfin is associated with Hippo pathway activation. Such action on cardiac Hippo pathway mediates mitochondrial damage and cardiomyopathy.
化疗是癌症治疗的常用临床策略。然而，伴随的心肌病使癌症患者面临另一种危及生命的情况的风险。Hippo 通路已知在癌症发生和心脏病中都发挥着关键作用，但 Hippo 通路的激活是否介导化疗诱导的心肌病仍不清楚。在人乳腺癌细胞中，阿霉素（DOX）显著诱导 Hippo 激酶 MST1 的上调，YAP 的抑制性磷酸化，线粒体损伤，细胞活力降低和细胞凋亡增加。Mst1-siRNA 转染可有效抑制 Hippo 通路激活，从而提高细胞存活率，并减轻线粒体损伤和细胞凋亡。另一种抗癌药物 YAP 抑制剂维替泊芬也可降低癌细胞活力、诱导细胞凋亡和线粒体损伤。慢性 DOX（每周 4mg/kg，共 6 周）治疗可引起线粒体损伤和功能障碍、氧化应激和心脏纤维化，而急性 DOX 治疗（单次 16mg/kg 注射）也可引起心肌氧化应激和线粒体异常。慢性维替泊芬（2 个月）治疗可导致心肌病表型与慢性 DOX 方案相似。在心脏过表达激酶失活突变 MST1 基因的转基因小鼠中，与野生型同窝仔相比，DOX 的这些不良心脏作用明显减弱。DOX 和维替泊芬的抗癌作用均与 Hippo 通路的激活有关。这种对心脏 Hippo 通路的作用介导了线粒体损伤和心肌病。
