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lüll Adenoviral melanoma differentiation-associated gene 7 induces apoptosis in lung cancer cells through mitochondrial permeability transition-independent cytochrome c release Pataer A; Chada S; Hunt KK; Roth JA; Swisher SGJ Thorac Cardiovasc Surg 2003[Jun]; 125 (6): 1328-35OBJECTIVE: Melanoma differentiation-associated gene 7 is a novel tumor suppressor gene that induces apoptosis in lung cancer cells when delivered by adenoviral gene transfer as Ad-mda7. The mechanisms of action are not well defined but may involve release of cytochrome c from the mitochondria with subsequent caspase activation. METHODS: The lung cancer cell lines A549 and H1299 were transduced with Ad-mda7, adenovirus containing the gene for p53 (Ad-p53), and control adenoviral luciferase vectors. Staurosporine was used as a positive control to induce cytochrome c release through mitochondrial permeability transition-dependent pores, whereas cyclosporine (INN: ciclosporin) was used to specifically inhibit these mitochondrial permeability transition-dependent pores. Apoptosis was evaluated with fluorescence-activated cell sorting analysis of subdiploid populations and mitochondrial membrane potential changes with tetramethylrhodamine ethylester perchlorate. RESULTS: Melanoma differentiation-associated gene 7, transduced by Ad-mda7 into H1299 and A549 lung cancer cells, resulted in sharp increases in cytosolic cytochrome c levels followed by induction of apoptosis and cellular death. The release of cytochrome c from the mitochondria occurred without changes in the mitochondrial membrane potential. Unlike staurosporine treatment, transduction with Ad-p53 and Ad-mda7 caused releases of cytochrome c and apoptosis that were not blocked by cyclosporine, suggesting a mitochondrial permeability transition pore-independent pathway. CONCLUSIONS: Ad-mda7 induces apoptosis in lung cancer cells through mitochondrial cytochrome c release in a process that is not dependent on mitochondrial membrane potential changes and occurs through mitochondrial permeability transition-independent pores. This unique mechanism of action may allow treatment of patients with lung cancer resistant to mitochondrial permeability transition-dependent cell death processes.|*Genes, Tumor Suppressor/physiology[MESH]|Adenoviridae[MESH]|Apoptosis/*drug effects[MESH]|Caspases/metabolism[MESH]|Cyclosporine/pharmacology[MESH]|Cytochrome c Group/*metabolism[MESH]|Enzyme Activation[MESH]|Gene Transfer Techniques[MESH]|Genes, p53/physiology[MESH]|Humans[MESH]|Interleukins/*pharmacology[MESH]|Lung Neoplasms/*pathology[MESH]|Membrane Potentials/physiology[MESH]|Mitochondria/*enzymology/physiology[MESH]|Staurosporine/pharmacology[MESH]|Transduction, Genetic[MESH]|Tumor Cells, Cultured[MESH] |