Taxol-induced mitochondrial stress in melanoma cells is mediated by activation of c-Jun N-terminal kinase (JNK) and p38 pathways via uncoupling protein 2.
Taxol (paclitaxel) is a new antineoplastic drug that has shown promise in the treatment of different tumor types. However, the molecular mechanisms governing taxol-induced apoptosis are poorly understood. Activation of mitogen-activated protein (MAP) kinases is induced by a wide variety of external stress signals and may lead to apoptosis. Therefore, we challenged the human melanoma cell lines A375 and BLM with taxol and characterized the molecular mechanisms regulating taxol-induced apoptosis. Taxol resulted in the activation of apoptosis signal regulated kinase (ASK)1, c-jun NH(2)-terminal kinase (JNK), p38(MAPK) and extracellular-regulated kinase (ERK) together with the downregulation of uncoupling protein 2 (UCP2). In addition, reactive oxygen species (ROS) were induced and DNA-binding activity of the transcription factors AP-1, ATF-2 and ELK-1 was enhanced. Ultimately, cytochrome c was released, and caspases-9 and -3 as well as PARP were cleaved. Pretreatment of melanoma cells with the JNK inhibitor (SP600125) or the p38 inhibitor (SB203580) blocked taxol-induced UCP2 downregulation, ROS generation and apoptosis, whereas the ERK inhibitor (PD98059) had no such effect. Our data provide evidence that taxol-induced mitochondrial stress occurs through the activation of both JNK and p38 pathways, and suggest a novel role for UCP2 in the modulation of taxol-induced apoptosis of melanoma cells.
Selimovic
Denis
D
Laboratory for Molecular Tumour Therapy, Department of Dermatology, University Hospital of Duesseldorf, Duesseldorf, Germany.
Hassan
Mohamed
M
Haikel
Youssef
Y
Hengge
Ulrich R
UR
D000111:Acetylcysteine / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D017239:Paclitaxel / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D016166:Free Radical Scavengers; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D017239:Paclitaxel; D000111:Acetylcysteine