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Originally published In Press as doi:10.1074/jbc.M408190200 on December 22, 2004

J. Biol. Chem., Vol. 280, Issue 13, 12486-12493, April 1, 2005
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Bid Mediates Apoptotic Synergy between Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and DNA Damage*{boxs}

V. Courtney Broaddus{ddagger}§, Tobias B. Dansen¶, Keith S. Abayasiriwardana{ddagger}, Shannon M. Wilson{ddagger}, Andrew J. Finch¶, Lamorna Brown Swigart¶, Abigail E. Hunt¶, and Gerard I. Evan¶

From the {ddagger}Lung Biology Center, San Francisco General Hospital, University of California San Francisco, San Francisco, California 94143-0854 and Cancer Research Institute, University of California San Francisco Comprehensive Cancer Center, San Francisco, California 94143-0875

The death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), has shown great promise for inducing apoptosis selectively in tumors. Although many tumor cells are resistant to TRAIL-induced apoptosis alone, they can often be sensitized by co-treatment with DNA-damaging agents such as etoposide. However, the molecular mechanism underlying this therapeutically important synergy is unknown. We explored the mechanism mediating TRAIL-DNA damage apoptotic synergy in human mesothelioma cells, a tumor type particularly refractory to existing therapies. We show that Bid, a cytoplasmic Bcl-2 homology domain 3-containing protein activated by caspase 8 in response to TRAIL ligation, is essential for TRAIL-etoposide apo-ptotic synergy and, furthermore, that exposure to DNA damage primes cells to induction of apoptosis by otherwise sublethal levels of activated Bid. Finally, we show that the extensive caspase 8 cleavage seen during TRAIL-etoposide synergy is a consequence and not a cause of the apoptotic cascade activated downstream of Bid. These data indicate that TRAIL-etoposide apoptotic synergy arises because DNA damage increases the inherent sensitivity of cells to levels of TRAIL-activated Bid that would otherwise be insufficient for apoptosis. Such studies indicate how the adroit combination of differing proapoptotic and sublethal signals can provide an effective strategy for treating refractory tumors.

Received for publication, July 20, 2004 , and in revised form, December 14, 2004.

* This work was supported by National Institutes of Health Grants RO1ES08985 and RO1CA95671 (to V. C. B.), 1R01CA098018-01 (to G. I. E.), European Molecular Biology Organization Fellowship ALTF 477-2001 (to T. B. D.), and the Daiichi Cancer Research Program (to G. I. E., A. J. F., and A. E. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{boxs} The on-line version of this article (available at http://www.jbc.org) contains a supplemental movie.

§ To whom correspondence should be addressed: Lung Biology Center, Box 0854, University of California San Francisco, San Francisco, CA 94143-0854; Tel.: 415-206-3513; Fax: 415-206-4123; E-mail: sfcourt{at}itsa.ucsf.edu.


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