Smac/DIABLO release from mitochondria and XIAP inhibition are essential to limit clonogenicity of Type I tumor cells after TRAIL receptor stimulation

Jannie Borst (1) , Chiel Maas (1) , Inge Verbrugge (1) , Evert de Vries (1) , Gleb Savich (1) , Lambertus W van de Kooij (1) , Stephen W Tait (1)

1 Division of Immunology

Death receptors such as Fas/CD95 and TRAIL receptors engage the extrinsic pathway for caspase activation, but also couple to the intrinsic mitochondrial route. In so-called Type II cells, death receptors require the mitochondrial pathway for apoptotic execution, whereas in Type I cells they reportedly do not. For established tumor cell lines, the Type I/Type II distinction is based on short-term apoptosis assays. We report here that the mitochondrial pathway is essential for apoptotic execution of Type I tumor cells by death receptors, when long-term clonogenicity is taken into account. A blockade of the mitochondrial pathway in Type I tumor cells - by RNA interference for Bid or Bcl-2 overexpression - reduced effector caspase activity and mediated significant clonogenic resistance to TRAIL. Downstream from the mitochondria, Caspase-9 did not contribute to clonogenic death of TRAIL-treated Type I cells. Rather, the release of Smac/DIABLO and the inhibition of XIAP activity proved to be crucial for full effector caspase activity and clonogenic execution. Thus, in Type I cells the intrinsic pathway downstream from death receptors is not redundant, but limits clonogenicity by virtue of Smac/DIABLO release and XIAP inhibition. This finding is relevant for cancer therapy with death receptor agonists.

Mots clés: TRAIL; mitochondria; Type I; XIAP; death receptor

Jannie Borst, Chiel Maas, Inge Verbrugge, Evert de Vries, Gleb Savich, et al.. Smac/DIABLO release from mitochondria and XIAP inhibition are essential to limit clonogenicity of Type I tumor cells after TRAIL receptor stimulation. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.39⟩. ⟨hal-00526840⟩