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A Smac Mimetic Rescue Screen Reveals Roles for Inhibitor of Apoptosis Proteins in Tumor Necrosis Factor- Signaling

Oncology Disease Area and Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts

Requests for reprints: Leigh Zawel, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139. Phone: 617-871-3455; Fax: 617-871-5783; E-mail: leigh.zawel{at}novartis.com.

Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor (TNF) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNF signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNF induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNF-mediated apoptosis. [Cancer Res 2007;67(24):11493–8]

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