Autocrine TNFalpha Signaling Renders Human Cancer Cells Susceptible to Smac-mimetic-induced Apoptosis

Cancer Cell. 2007 Nov;12(5):445-56. doi: 10.1016/j.ccr.2007.08.029.

Abstract

A small-molecule mimetic of Smac/Diablo that specifically counters the apoptosis-inhibiting activity of IAP proteins has been shown to enhance apoptosis induced by cell surface death receptors as well as chemotherapeutic drugs. Survey of a panel of 50 human non-small-cell lung cancer cell lines has revealed, surprisingly, that roughly one-quarter of these lines are sensitive to the treatment of Smac mimetic alone, suggesting that an apoptotic signal has been turned on in these cells and is held in check by IAP proteins. This signal has now been identified as the autocrine-secreted cytokine tumor necrosis factor alpha (TNFalpha). In response to autocrine TNFalpha signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lung Neoplasms / metabolism*
  • Mice
  • Mice, Nude
  • Mitochondrial Proteins / metabolism*
  • Models, Biological
  • Neoplasm Transplantation
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Tumor Necrosis Factor-alpha
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Caspase 8