Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: He, Gui-Wei, Günther, Claudia, Thonn, Veronika, Yu, Yu-Qiang, Martini, Eva, Buchen, Barbara, Neurath, Markus F., Stürzl, Michael, Becker, Christoph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
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
_version_ 1783242264137433088
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
work_keys_str_mv AT heguiwei regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice
AT guntherclaudia regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice
AT thonnveronika regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice
AT yuyuqiang regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice
AT martinieva regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice
AT buchenbarbara regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice
AT neurathmarkusf regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice
AT sturzlmichael regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice
AT beckerchristoph regressionofapoptosisresistantcolorectaltumorsbyinductionofnecroptosisinmice