Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice

Gui-Wei He, Claudia Günther, Veronika Thonn, Yu-Qiang Yu, Eva Martini, Barbara Buchen, Markus F Neurath, Michael Stürzl, Christoph Becker

Research output: Contribution to journalOriginal Articlepeer-review

Abstract

Cancer cells often acquire capabilities to evade cell death induced by current chemotherapeutic treatment approaches. Caspase-8, a central initiator of death receptor-mediated apoptosis, for example, is frequently inactivated in human cancers via multiple mechanisms such as mutation. Here, we show an approach to overcome cell death resistance in caspase-8-deficient colorectal cancer (CRC) by induction of necroptosis. In both a hereditary and a xenograft mouse model of caspase-8-deficient CRC, second mitochondria-derived activator of caspase (SMAC) mimetic treatment induced massive cell death and led to regression of tumors. We further demonstrate that receptor-interacting protein kinase 3 (RIP3), which is highly expressed in mouse models of CRC and in a subset of human CRC cell lines, is the deciding factor of cancer cell susceptibility to SMAC mimetic-induced necroptosis. Thus, our data implicate that it may be worthwhile to selectively evaluate the efficacy of SMAC mimetic treatment in CRC patients with caspase-8 deficiency in clinical trials for the development of more effective personalized therapy.

Original languageEnglish
Pages (from-to)1655-1662
Number of pages8
JournalJournal of experimental medicine
Volume214
Issue number6
DOIs
Publication statusPublished - 5 Jun 2017
Externally publishedYes

Keywords

  • Animals
  • Apoptosis
  • Caspase 8/metabolism
  • Colon/pathology
  • Colorectal Neoplasms/enzymology
  • Enterocytes/metabolism
  • HT29 Cells
  • Humans
  • Mice
  • Mitochondrial Proteins/metabolism
  • Necrosis
  • Xenograft Model Antitumor Assays

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