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A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling.

Gaither, Alex and Porter, Dale and Yao, Yao and Borawski, Jason and Yang, Guang and Donovan, Jerry and Sage, David and Slisz, Joanna and Tran, Mary and Straub, Christopher and Ramsey, Timothy and Iourgenko, Vadim and Huang, Alan and Chen, Yan and Schlegel, Robert and Labow, Mark and Fawell, Stephen and Sellers, William and Zawel, Leigh (2007) A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling. Cancer Research, 67 (24). pp. 11493-11498. ISSN 1538-7445

Abstract

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 (TNFalpha) 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 TNFalpha signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFalpha induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFalpha-mediated apoptosis.

Item Type: Article
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Additional Information: free final full text version available at publisher's official URL; author can archive post-print (ie final draft post-refereeing); Authors final version may be deposited on institutional website/ repository if required by institution
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Date Deposited: 14 Dec 2009 14:01
Last Modified: 31 Jan 2013 01:19
URI: https://oak.novartis.com/id/eprint/337

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