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Involvement of Proapoptotic Molecules Bax and Bak in Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Mitochondrial Disruption and Apoptosis

Differential Regulation of Cytochrome c and Smac/DIABLO Release¹

Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Greenebaum Cancer Center, Baltimore, Maryland 21201-1180 [K. K., R. K. S.]; Center for Apoptosis Research and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [S. M. S., E. S. A.]; Departments of Medicine and Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104 [C. B. T.]; Howard Hughes Medical Institute, Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [S. J. K.]; and Institute of Human Virology/University of Maryland Biotechnology Institute, Baltimore, Maryland 21201-1180 [J. L. B.]

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L induces apoptosis in a wide variety of cancer and transformed cells. Activation of BID, a "BH3-domain-only" Bcl-2 family member, triggers the oligomerization of proapoptotic family members Bak or Bax, resulting in the release of mitochondrial proteins to cytosol. In this study, we have shown the importance of Bax and Bak in TRAIL-induced apoptosis by studying in murine embryonic fibroblasts (MEFs) from Bax^-/- and Bak^-/- animals. TRAIL induced cytochrome c release and apoptosis in wild-type, Bid^-/-, Bax^-/-, or Bak^-/- MEFs, but not in Bax^-/- Bak^-/- double knockout (DKO) MEFs. Bid, which functions upstream of cytochrome c release, was cleaved in all of the knockout cells except in Bid^-/- MEFs. The release of cytochrome c was correlated with caspase-9 activity. TRAIL increased caspase-3 activity in all of the cells except in DKO cells. TRAIL-induced drop in mitochondrial membrane potential was not observed in DKO MEFs. Unlike cytochrome c release, TRAIL-induced Smac/DIABLO release was blocked in Bid^-/-, Bax^-/-, Bak^-/-, or DKO MEFs, suggesting the differential regulation of these mitochondrial proteins during apoptosis. The apoptotic events downstream of mitochondria were intact in DKO MEFs, because microinjection of cytochrome c, or ectopic expression of mature Smac/DIABLO or pretreatment of Smac N7 peptide completely restored TRAIL sensitivity. In conclusion, the data suggest that Bax and Bak differentially regulate the release of cytochrome c and Smac/DIABLO from mitochondria, and Smac/DIABLO can be used to sensitize cells that are deficient in Bax and Bak genes, or resistant to TRAIL.

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