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J Thorac Cardiovasc Surg 2003;125:1328-1335
© 2003 The American Association for Thoracic Surgery

General Thoracic Surgery

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

From the Section of Thoracic Molecular Oncology, Departments of Thoracic and Cardiovascular Surgery^a and Surgical Oncology,^b The University of Texas M.D. Anderson Cancer Center, and Introgen Therapeutics Inc,^c Houston, Tex.

Supported by grants from the National Cancer Institute and the National Institutes of Health (P01 CA78778-01A1 to J.A.R. and S.G.S., SBIR S/C 1R43 CA86587-1 to S.G.S. and S.C., and SPORE 2P50-CA70970-04), by gifts to the Division of Surgery from Tenneco and Exxon for the Core Laboratory Facility, by the University of Texas M. D. Anderson Cancer Center Support Core Grant (CA 16672), by donations from the Charles Rogers Memorial and Gene Therapy Donor funds, by a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8), by the W. M. Keck Foundation, and by a sponsored research agreement with Introgen Therapeutics, Inc (SR93-004-1).

Received for publication May 20, 2002. Revisions requested July 8, 2002; revisions received July 22, 2002. Accepted for publication Aug 14, 2002. Address for reprints: Stephen G. Swisher, MD, Department of Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 445, Houston, TX 77030 (E-mail: sswisher{at}mdanderson.org).

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.

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