Smac mimetics and TNFalpha: a dangerous liaison?
Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. It has been thought that small-molecule mimetics of Smac, an endogenous IAP antagonist, might potentiate apoptosis in cancer cells by promoting caspase activation. However, three recent papers, two in Cell (Vince et al., 2007; Varfolomeev et al., 2007) and one in Cancer Cell (Petersen et al., 2007), now report that Smac mimetics primarily kill cancer cells via a different mechanism, the induction of autoubiquitination and degradation of cIAPs, which culminates in TNFalpha-mediated cell death.
Wu
Hao
H
Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA. haowu@med.cornell.edu
Tschopp
Jurg
J
Lin
Su-Chang
SC
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha