Department of Clinical Pharmacotherapeutics, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
Cardiovasc Toxicol. 2022 May;22(5):462-476. doi: 10.1007/s12012-022-09726-w. Epub 2022 Feb 21.
Doxorubicin (DOX) is a potent chemotherapeutic agent; however, it causes severe heart injury via apoptosis induction in many patients. DOX-induced cardiotoxicity is attenuated by activated autophagy in the heart. We previously found that programmed cell death 1 (Pdcd1), an immune checkpoint receptor, inhibits DOX-induced cardiomyocyte apoptosis. In this study, we investigated whether autophagy contributes to the protective role of Pdcd1 against DOX-induced cardiomyocyte apoptosis. We also examined the role of Pdcd1 in DOX-induced apoptosis in cancer cells. Rat cardiomyocyte cell line H9c2 and human cancer cell lines K562 and MCF-7 were transfected with Pdcd1-encoding plasmid DNA to establish Pdcd1-overexpressing cells. Apoptosis and autophagy were determined using a luciferase assay. In H9c2 cells, DOX-induced apoptosis and viability reduction occurred through caspase activation. In particular, Pdcd1 overexpression activated the autophagy pathway through the inhibition of the mammalian target of rapamycin, a major negative regulator of autophagy. Moreover, it prevented DOX-induced cardiomyocyte apoptosis; a similar cardioprotection was observed when normal H9c2 cells (without Pdcd1 overexpression) were treated with rapamycin, an autophagy inducer, before the DOX treatment. Conversely, in cancer cells, Pdcd1 overexpression increased both basal and DOX-induced apoptosis. The role of Pdcd1 in DOX-induced apoptosis in cardiomyocytes and cancer cells was opposing. Pdcd1 signaling prevented DOX-induced apoptosis in cardiomyocytes, through autophagy induction; it enhanced DOX-induced apoptosis in cancer cells. Therefore, Pdcd1 could be a critical molecule for more effective and safer DOX chemotherapy.
多柔比星（DOX）是一种有效的化疗药物；然而，它会通过诱导细胞凋亡导致许多患者严重的心脏损伤。在心脏中，激活的自噬可以减轻多柔比星引起的心脏毒性。我们之前发现，程序性细胞死亡 1（Pdcd1），一种免疫检查点受体，可抑制多柔比星诱导的心肌细胞凋亡。在这项研究中，我们研究了自噬是否有助于 Pdcd1 抵抗多柔比星诱导的心肌细胞凋亡的保护作用。我们还检查了 Pdcd1 在多柔比星诱导的癌细胞凋亡中的作用。用 Pdcd1 编码质粒 DNA 转染大鼠心肌细胞系 H9c2 和人癌细胞系 K562 和 MCF-7，建立 Pdcd1 过表达细胞。用荧光素酶测定法测定细胞凋亡和自噬。在 H9c2 细胞中，多柔比星诱导的凋亡和活力降低是通过半胱氨酸天冬氨酸蛋白酶（caspase）激活来实现的。特别是，Pdcd1 过表达通过抑制哺乳动物雷帕霉素靶蛋白（mTOR），即自噬的主要负调节剂，激活自噬途径。此外，它可以防止多柔比星诱导的心肌细胞凋亡；在用自噬诱导剂雷帕霉素预处理多柔比星处理之前，正常 H9c2 细胞（无 Pdcd1 过表达）也观察到类似的心脏保护作用。相反，在癌细胞中，Pdcd1 过表达增加了基础和多柔比星诱导的凋亡。Pdcd1 在心肌细胞和癌细胞中诱导的多柔比星诱导的凋亡中的作用是相反的。Pdcd1 信号通过诱导自噬来防止多柔比星诱导的心肌细胞凋亡；它增强了多柔比星诱导的癌细胞凋亡。因此，Pdcd1 可能是更有效和更安全的多柔比星化疗的关键分子。
