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 language | English |
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Pages (from-to) | 1655-1662 |
Number of pages | 8 |
Journal | Journal of experimental medicine |
Volume | 214 |
Issue number | 6 |
DOIs | |
Publication status | Published - 5 Jun 2017 |
Externally published | Yes |
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