Adenoviral melanoma differentiation-associated gene 7 induces apoptosis in lung cancer cells through mitochondrial permeability transition-independent cytochrome c release.

Abstract

OBJECTIVE:

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.

• Authors: Abujiang Pataer, Sunil Chada, Kelly K Hunt, Jack A Roth, Stephen G Swisher
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 125 Issue 6 Pg. 1328-35 (Jun 2003) ISSN: 0022-5223 [Print] United States
• PMID: 12830052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytochrome c Group
• Interleukins
• interleukin-24
• Cyclosporine
• Caspases
• Staurosporine

Topics

• Adenoviridae
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cyclosporine (pharmacology)
• Cytochrome c Group (metabolism)
• Enzyme Activation
• Gene Transfer Techniques
• Genes, Tumor Suppressor (physiology)
• Genes, p53 (physiology)
• Humans
• Interleukins (pharmacology)
• Lung Neoplasms (pathology)
• Membrane Potentials (physiology)
• Mitochondria (enzymology, physiology)
• Staurosporine (pharmacology)
• Transduction, Genetic
• Tumor Cells, Cultured