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TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO
Yibin Deng1, Yahong Lin, Xiangwei Wu
1Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract:
Recent reports suggest that a cross-talk exists between apoptosis pathways mediated by mitochondria and cell death receptors. In the present study, we report that mitochondrial events are required for apoptosis induced by the cell death ligand TRAIL (TNF-related apoptosis-inducing ligand) in human cancer cells. We show that the Bax null cancer cells are resistant to TRAIL-induced apoptosis. Bax deficiency has no effect on TRAIL-induced caspase-8 activation and subsequent cleavage of Bid; however, it results in an incomplete caspase-3 processing because of inhibition by XIAP. Release of Smac/DIABLO from mitochondria through the TRAIL-caspase-8-tBid-Bax cascade is required to remove the inhibitory effect of XIAP and allow apoptosis to proceed. Inhibition of caspase-9 activity has no effect on TRAIL-induced caspase-3 activation and cell death, whereas expression of the active form of Smac/DIABLO in the cytosol is sufficient to reconstitute TRAIL sensitivity in Bax-deficient cells. Our results show for the first time that Bax-dependent release of Smac/DIABLO, not cytochrome c, from mitochondria mediates the contribution of the mitochondrial pathway to death receptor-mediated apoptosis.
Insights
Mitochondrial Bax is essential for TRAIL-induced apoptosis in cancer cells by enabling Smac/DIABLO release, which overcomes XIAP inhibition and allows cell death. This clarifies the link between death receptors and mitochondria.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Cross-talk between mitochondrial and death receptor pathways in apoptosis is reported.
- TNF-related apoptosis-inducing ligand (TRAIL) triggers apoptosis via death receptors.
Purpose of the Study:
- To investigate the role of mitochondrial events in TRAIL-induced apoptosis in human cancer cells.
- To elucidate the specific mitochondrial proteins involved in the TRAIL pathway.
Main Methods:
- Utilized Bax-null cancer cells to assess resistance to TRAIL-induced apoptosis.
- Analyzed caspase activation (caspase-8, caspase-3), Bid cleavage, and Smac/DIABLO release.
- Investigated the effect of caspase-9 inhibition and Smac/DIABLO expression on TRAIL sensitivity.
Main Results:
- Bax-null cells are resistant to TRAIL-induced apoptosis.
- Bax deficiency impairs caspase-3 processing due to XIAP inhibition, despite intact caspase-8 activation and Bid cleavage.
- TRAIL-induced apoptosis requires Bax-dependent release of Smac/DIABLO from mitochondria to inhibit XIAP.
Conclusions:
- Mitochondrial Bax is crucial for TRAIL-induced apoptosis by facilitating Smac/DIABLO release.
- Smac/DIABLO release, not cytochrome c, mediates the mitochondrial contribution to death receptor-induced apoptosis.
- This pathway highlights a novel mechanism in cancer cell death regulation.