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Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice
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 a...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460989/ https://www.ncbi.nlm.nih.gov/pubmed/28476895 http://dx.doi.org/10.1084/jem.20160442 |
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author | He, Gui-Wei Günther, Claudia Thonn, Veronika Yu, Yu-Qiang Martini, Eva Buchen, Barbara Neurath, Markus F. Stürzl, Michael Becker, Christoph |
author_facet | He, Gui-Wei Günther, Claudia Thonn, Veronika Yu, Yu-Qiang Martini, Eva Buchen, Barbara Neurath, Markus F. Stürzl, Michael Becker, Christoph |
author_sort | He, Gui-Wei |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5460989 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54609892017-12-05 Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice He, Gui-Wei Günther, Claudia Thonn, Veronika Yu, Yu-Qiang Martini, Eva Buchen, Barbara Neurath, Markus F. Stürzl, Michael Becker, Christoph J Exp Med Research Articles 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. The Rockefeller University Press 2017-06-05 /pmc/articles/PMC5460989/ /pubmed/28476895 http://dx.doi.org/10.1084/jem.20160442 Text en © 2017 He et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles He, Gui-Wei Günther, Claudia Thonn, Veronika Yu, Yu-Qiang Martini, Eva Buchen, Barbara Neurath, Markus F. Stürzl, Michael Becker, Christoph Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice |
title | Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice |
title_full | Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice |
title_fullStr | Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice |
title_full_unstemmed | Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice |
title_short | Regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice |
title_sort | regression of apoptosis-resistant colorectal tumors by induction of necroptosis in mice |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460989/ https://www.ncbi.nlm.nih.gov/pubmed/28476895 http://dx.doi.org/10.1084/jem.20160442 |
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