Smac mimetics and TNFalpha: a dangerous liaison?

Cell. 2007 Nov 16;131(4):655-8. doi: 10.1016/j.cell.2007.10.042.


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.

Publication types

  • Review
  • Comment

MeSH terms

  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Molecular Mimicry*
  • NF-kappa B / metabolism
  • Neoplasms / metabolism*
  • Signal Transduction / physiology
  • Tumor Necrosis Factor-alpha / metabolism*


  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha