Induction of indoleamine 2, 3-dioxygenase by death receptor activation contributes to apoptosis of melanoma cells via mitochondrial damage-dependent ROS accumulation.
Although the induction of indoleamine 2, 3-dioxygenase (IDO) by several agents is well established, the mechanisms of its transcriptional regulation and those regulating its function as apoptotic mediator seem to be complex, agent-dependent, and cell type-specific. Besides their pro-apoptotic activity in melanoma cells, both anti-Fas agonist antibody (CH11) and the tumor necrosis factor (TNF)-alpha were found to induce IDO gene expression, the activation of apoptosis signal-regulating kinase (ASK1), and the activation of both c-Jun N-terminal kinase (JNK) and NF-kappaB pathways. In addition, the treatment of melanoma cells with CH11 or TNF-alpha induced the loss of mitochondrial membrane potential (Deltapsim), the accumulation of reactive oxygen species (ROS), the phosphorylation of Fas-associated domain (FADD), the cleavage of caspase-8, and truncation of Bid. Using RNA interference and pharmacological inhibitors, we could confirm the pro-apoptotic activity of IDO and address the mechanisms, which are responsible for its transcriptional regulation and the modulation of its pro-apoptotic activity during death receptor activation in melanoma cells. Thus, our data confirm the pro-apoptotic activity of IDO and provide an insight into the molecular mechanism of TNF-alpha and CH11-induced IDO expression, and the mechanism whereby IDO induces apoptosis of melanoma cells.
Clinic of Dermatology, University Hospital of Duesseldorf, Germany.
Turgut
T
Cetindere
Sandeep
S
Nambiar
Simeon
S
Santourlidis
Frank
F
Essmann
Mohamed
M
Hassan
D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053218:Receptors, Death Domain / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051023:BH3 Interacting Domain Death Agonist Protein; D053200:Fas-Associated Death Domain Protein; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D053181:Caspase 8