Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2J7, Canada.
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta T6G 2J7, Canada.
Sci Transl Med. 2019 Feb 6;11(478). doi: 10.1126/scitranslmed.aau8866.
Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Although inhibition of p53 shows benefit in preclinical heart failure models, it would not be an attractive adjuvant therapy for CIC, because it would prevent tumor regression. A p53-targeting therapy that would decrease chemotherapy-induced apoptosis in the myocardium and, at the same time, enhance apoptosis in the tumor would be ideal. Here, we propose that differences in oxygen tension between the myocardium and the tumor could provide a platform for redox-dependent tissue-specific therapies. We show by coimmunoprecipitation and mass spectrometry that the redox-regulated pyruvate kinase muscle 2 (PKM2) directly binds with p53 and that the redox status of cysteine-423 of tetrameric (but not monomeric) PKM2 is critical for the differential regulation of p53 transcriptional activity. Tetrameric PKM2 suppresses p53 transcriptional activity and apoptosis in a high oxidation state but enhances them in a low oxidation one. We show that the oxidation state (along with cysteine-423 oxidation) is higher in the heart compared to the tumor of the same animal. Treatment with TEPP-46 (a compound that stabilizes tetrameric PKM2) suppressed doxorubicin-induced cardiomyocyte apoptosis, preventing cardiac dysfunction, but enhanced cancer cell apoptosis and tumor regression in the same animals in lung cancer models. Thus, our work suggests that redox-dependent differences in common proteins expressed in the myocardium and tumor can be exploited therapeutically for tissue selectivity in CIC.
化疗诱导的心脏毒性（CIC）是一种常见的临床问题，会影响有效的抗癌治疗。许多化疗药物（包括蒽环类药物，如多柔比星）在肿瘤中和非特异性地在心脏中诱导促凋亡转录因子 p53，从而促进心力衰竭。尽管抑制 p53 在心力衰竭的临床前模型中显示出益处，但它不会成为 CIC 的一种有吸引力的辅助治疗方法，因为它会阻止肿瘤消退。一种针对 p53 的治疗方法，可减少心肌中的化疗诱导的细胞凋亡，同时增强肿瘤中的细胞凋亡，将是理想的。在这里，我们提出心肌和肿瘤之间的氧张力差异可以为基于氧化还原的组织特异性治疗提供一个平台。我们通过共免疫沉淀和质谱法表明，氧化还原调节的丙酮酸激酶肌肉 2（PKM2）直接与 p53 结合，并且四聚体（而非单体）PKM2 的半胱氨酸-423 的氧化还原状态对于 p53 转录活性的差异调节至关重要。四聚体 PKM2 在高氧化状态下抑制 p53 转录活性和细胞凋亡，但在低氧化状态下增强它们。我们表明，与同一动物的肿瘤相比，心脏的氧化状态（以及半胱氨酸-423 氧化）更高。用 TEPP-46（一种稳定四聚体 PKM2 的化合物）治疗可抑制多柔比星诱导的心肌细胞凋亡，防止心脏功能障碍，但在肺癌模型中增强了相同动物的癌细胞凋亡和肿瘤消退。因此，我们的工作表明，在心肌和肿瘤中表达的常见蛋白的氧化还原依赖性差异可以被利用来治疗 CIC 中的组织选择性。
