Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11936-41. Epub 2010 Jun 14.

Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression.External

Petersen, S. L., Peyton, M., Minna, J. D., Wang, X.,
--- - Howard Hughes Medical Institute and Department of Biochemistry and Hamon Center for Therapeutic Oncology Research and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Smac mimetics target cancer cells in a TNFalpha-dependent manner, partly via proteasome degradation of cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2. Degradation of cIAPs triggers the release of receptor interacting protein kinase (RIPK1) from TNF receptor I (TNFR1) to form a caspase-8 activating complex together with the adaptor protein Fas-associated death domain (FADD). We report here a means through which cancer cells mediate resistance to Smac mimetic/TNFalpha-induced apoptosis and corresponding strategies to overcome such resistance. These human cancer cell lines evades Smac mimetic-induced apoptosis by up-regulation of cIAP2, which although initially degraded, rebounds and is refractory to subsequent degradation. cIAP2 is induced by TNFalpha via NF-kappaB and modulation of the NF-kappaB signal renders otherwise resistant cells sensitive to Smac mimetics. In addition, other signaling pathways, including phosphatidyl inositol-3 kinase (PI3K), have the potential to concurrently regulate cIAP2. Using the PI3K inhibitor, LY294002, cIAP2 up-regulation was suppressed and resistance to Smac mimetics-induced apoptosis was also overcome.
PMID: 20547836External
Arrow2 In vitro interaction Arrow2 In vivo interaction Arrow2 Characterization Arrow2 Functional role Arrow2 top
In vivo interaction
  Endogenous
expression
Overexpression DD1 DD2 Reference
Family DD1 DD2 Method Species Region Species Region
DD RIP Link TNFR1 Co-immunoprecipitation H2009 20547836
DED Caspase8 Link FADD Co-immunoprecipitation H2009 20547836
(Link: click this icon to show interactions only between the two corresponding DDs)