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Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2017
- Publisher :
- The Rockefeller University Press, 2017.
-
Abstract
- He et al. demonstrate that SMAC mimetic is efficient to target caspase-8–deficient colorectal cancer by induction of necroptosis. This study represents an attractive strategy for overcoming apoptosis resistance in colorectal cancer for the development of more effective personalized therapy.<br />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.
- Subjects :
- 0301 basic medicine
Programmed cell death
Colorectal cancer
Colon
Necroptosis
Immunology
Apoptosis
Caspase 8
Mitochondrial Proteins
03 medical and health sciences
Mice
Necrosis
0302 clinical medicine
medicine
Immunology and Allergy
Animals
Humans
Protein kinase A
Caspase
Research Articles
biology
Brief Definitive Report
medicine.disease
Xenograft Model Antitumor Assays
030104 developmental biology
Enterocytes
030220 oncology & carcinogenesis
Cancer cell
biology.protein
Cancer research
Colorectal Neoplasms
HT29 Cells
Subjects
Details
- Language :
- English
- ISSN :
- 15409538 and 00221007
- Volume :
- 214
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....1f69cc2b2d2f755fef34649016e07b5b