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Cancer Research 67, 11493-11498, December 15, 2007. doi: 10.1158/0008-5472.CAN-07-5173
© 2007 American Association for Cancer Research
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Priority Reports

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

Alex Gaither, Dale Porter, Yao Yao, Jason Borawski, Guang Yang, Jerry Donovan, David Sage, Joanna Slisz, Mary Tran, Christopher Straub, Tim Ramsey, Vadim Iourgenko, Alan Huang, Yan Chen, Robert Schlegel, Mark Labow, Stephen Fawell, William R. Sellers and Leigh Zawel

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 {alpha} (TNF{alpha}) 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{alpha} signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNF{alpha} induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNF{alpha}-mediated apoptosis. [Cancer Res 2007;67(24):11493–8]




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2007 by the American Association for Cancer Research.