Send to

Choose Destination
See comment in PubMed Commons below
Cell Death Differ. 2010 Oct;17(10):1613-23. doi: 10.1038/cdd.2010.39. Epub 2010 Apr 16.

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

Author information

Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.


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 using death receptor agonists.

[Indexed for MEDLINE]
Free full text
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group
    Loading ...
    Support Center