Autocrine TNFα Signaling Renders Human Cancer Cells Susceptible to Smac-Mimetic-Induced Apoptosis

Sean L. Petersen, Lai Wang, Asligul Yalcin-Chin, Lin Li, Michael Peyton, John Minna, Patrick Harran, Xiaodong Wang

Research output: Contribution to journalArticlepeer-review

474 Scopus citations


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 (TNFα). In response to autocrine TNFα signaling, the Smac mimetic promotes formation of a RIPK1-dependent caspase-8-activating complex, leading to apoptosis.

Original languageEnglish (US)
Pages (from-to)445-456
Number of pages12
JournalCancer Cell
Issue number5
StatePublished - Nov 13 2007



ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research


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