Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium
Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium
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DOI：
10.1042/bj20050285
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发表时间：
2005-07-15
影响因子：
4.1
通讯作者：
Kalyanaraman, B
中科院分区：
文献类型：
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作者：
Kalivendi, SV;Konorev, EA;Kalyanaraman, B
阿霉素（DOX）是一种广泛使用的抗肿瘤药物，可引起剂量依赖性心脏毒性。心脏线粒体是DOX化疗期间毒性的关键靶细胞器。提出的机制包括ROS（活性氧）的产生和线粒体钙稳态紊乱。在本研究中，我们探讨了线粒体活性氧和钙在胚胎大鼠心脏衍生的H9 c2细胞系和成年大鼠心肌细胞之间的机制联系。结果显示，DOX刺激转录因子NFAT（活化T淋巴细胞的核因子）的钙/钙调神经磷酸酶依赖性活化。用细胞内钙螯合剂预处理细胞可消除DOX诱导的核NFAT易位、Fas L（Fas配体）表达和半胱天冬酶活化，用靶向抗氧化剂Mito-Q（一种靶向抗氧化剂，由米托喹和米托醌的混合物组成）或用腺病毒过表达的抗氧化酶预处理细胞也是如此。GPx-1（谷胱甘肽过氧化物酶1），锰超氧化物歧化酶（锰超氧化物歧化酶）或NFAT的肽抑制剂的治疗也抑制DOX诱导的核NFAT易位。用Fas L中和抗体预处理细胞在细胞凋亡的初始阶段废除了DOX诱导的半胱天冬酶-8-和-3-样活性。我们的结论是，在通过NFAT信号传导机制刺激具有Fas L表达的心肌细胞中DOX诱导的凋亡的“内在和外在形式”中，DACA衍生的ROS和钙起关键作用。ROS和钙依赖性NFAT信号转导在阿霉素诱导的细胞凋亡的影响进行了讨论。
Doxorubicin (DOX), a widely used antitumour drug, causes dose-dependent cardiotoxicity. Cardiac mitochondria represent a critical target organelle of toxicity during DOX chemotherapy. Proposed mechanisms include generation of ROS (reactive oxygen species) and disturbances in mitochondrial calcium homoeostasis. In the present study, we probed the mechanistic link between mitochondrial ROS and calcium in the embryonic rat heart-derived H9c2 cell line and in adult rat cardiomyocytes. The results show that DOX stimulates calcium/calcineurin-dependent activation of the transcription factor NFAT (nuclear factor of activated T-lymphocytes). Pre-treatment of cells with an intracellular calcium chelator abrogated DOX-induced nuclear NFAT translocation, Fas L (Fas ligand) expression and caspase activation, as did pre-treatment of cells with a mitochondria-targeted antioxidant, Mito-Q (a mitochondria-targeted antioxidant consisting of a mixture of mitoquinol and mitoquinone), or with adenoviral-over-expressed antioxidant enzymes. Treatment with GPx-1 (glutathione peroxidase 1), MnSOD (manganese superoxide dismutase) or a peptide inhibitor of NFAT also inhibited DOX-induced nuclear NFAT translocation. Pre-treatment of cells with a Fas L neutralizing antibody abrogated DOX-induced caspase-8- and -3-like activities during the initial stages of apoptosis. We conclude that mitochondria-derived ROS and calcium play a key role in stimulating DOX-induced 'intrinsic and extrinsic forrns' of apoptosis in cardiac cells with Fas L expression via the NFAT signalling mechanism. Implications of ROS- and calcium-dependent NFAT signalling in DOX-induced apoptosis are discussed.