Bcl-xL is an oncogenic driver in colorectal cancer

Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family is mainly known for its pivotal role in the regulation of the mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits and in...

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Main Authors:	Scherr, Anna-Lena, Gdynia, Georg, Salou, Mariam, Radhakrishnan, Praveen, Duglova, Katarina, Heller, Anette, Keim, Sophia, Kautz, Nicole, Jassowicz, Adam, Elssner, Christin, He, You-Wen, Jaeger, Dirk, Heikenwalder, Mathias, Schneider, Martin, Weber, Achim, Roth, Wilfried, Schulze-Bergkamen, Henning, Koehler, Bruno Christian
Format:	Online
Language:	English
Published:	Nature Publishing Group 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108319/

id	pubmed-5108319
recordtype	oai_dc
spelling	pubmed-51083192016-11-15 Bcl-xL is an oncogenic driver in colorectal cancer Scherr, Anna-Lena Gdynia, Georg Salou, Mariam Radhakrishnan, Praveen Duglova, Katarina Heller, Anette Keim, Sophia Kautz, Nicole Jassowicz, Adam Elssner, Christin He, You-Wen Jaeger, Dirk Heikenwalder, Mathias Schneider, Martin Weber, Achim Roth, Wilfried Schulze-Bergkamen, Henning Koehler, Bruno Christian Original Article Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family is mainly known for its pivotal role in the regulation of the mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits and induce therapy resistance in cancer cells. Among anti-apoptotic Bcl-2 proteins, we found solely Bcl-xL strongly upregulated in human CRC specimens. In order to study protein function in the context of tumor initiation and progression in vivo, we generated a mouse model lacking Bcl-xL in intestinal epithelial cells (Bcl-xLIEC-KO). If challenged in an inflammation-driven tumor model, Bcl-xLIEC-KO mice showed a significantly reduced tumor burden with lower tumor numbers per animal and decreased tumor sizes. Analysis of cell death events by immunohistochemistry and immunoblotting revealed a striking increase of apoptosis in Bcl-xL-negative tumors. qRT-PCR and immunohistochemistry excluded changes in proliferative capacity and immune cell infiltration as reasons for the reduced tumor load and thereby identify apoptosis as key mechanism. Human CRC tissue was cultured ex vivo and treated with the small molecule compound ABT-737, which inhibits Bcl-xL and Bcl-2. Under ABT-737 treatment, the amount of apoptotic tumor cells significantly increased compared with controls, whereas proliferation levels remained unaltered. In summary, our findings identify Bcl-xL as a driver in colorectal tumorigenesis and cancer progression, making it a valuable target for clinical application. Nature Publishing Group 2016-08 2016-08-18 /pmc/articles/PMC5108319/ /pubmed/27537525 http://dx.doi.org/10.1038/cddis.2016.233 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Scherr, Anna-Lena Gdynia, Georg Salou, Mariam Radhakrishnan, Praveen Duglova, Katarina Heller, Anette Keim, Sophia Kautz, Nicole Jassowicz, Adam Elssner, Christin He, You-Wen Jaeger, Dirk Heikenwalder, Mathias Schneider, Martin Weber, Achim Roth, Wilfried Schulze-Bergkamen, Henning Koehler, Bruno Christian
spellingShingle	Scherr, Anna-Lena Gdynia, Georg Salou, Mariam Radhakrishnan, Praveen Duglova, Katarina Heller, Anette Keim, Sophia Kautz, Nicole Jassowicz, Adam Elssner, Christin He, You-Wen Jaeger, Dirk Heikenwalder, Mathias Schneider, Martin Weber, Achim Roth, Wilfried Schulze-Bergkamen, Henning Koehler, Bruno Christian Bcl-xL is an oncogenic driver in colorectal cancer
author_facet	Scherr, Anna-Lena Gdynia, Georg Salou, Mariam Radhakrishnan, Praveen Duglova, Katarina Heller, Anette Keim, Sophia Kautz, Nicole Jassowicz, Adam Elssner, Christin He, You-Wen Jaeger, Dirk Heikenwalder, Mathias Schneider, Martin Weber, Achim Roth, Wilfried Schulze-Bergkamen, Henning Koehler, Bruno Christian
author_sort	Scherr, Anna-Lena
title	Bcl-xL is an oncogenic driver in colorectal cancer
title_short	Bcl-xL is an oncogenic driver in colorectal cancer
title_full	Bcl-xL is an oncogenic driver in colorectal cancer
title_fullStr	Bcl-xL is an oncogenic driver in colorectal cancer
title_full_unstemmed	Bcl-xL is an oncogenic driver in colorectal cancer
title_sort	bcl-xl is an oncogenic driver in colorectal cancer
description	Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family is mainly known for its pivotal role in the regulation of the mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits and induce therapy resistance in cancer cells. Among anti-apoptotic Bcl-2 proteins, we found solely Bcl-xL strongly upregulated in human CRC specimens. In order to study protein function in the context of tumor initiation and progression in vivo, we generated a mouse model lacking Bcl-xL in intestinal epithelial cells (Bcl-xLIEC-KO). If challenged in an inflammation-driven tumor model, Bcl-xLIEC-KO mice showed a significantly reduced tumor burden with lower tumor numbers per animal and decreased tumor sizes. Analysis of cell death events by immunohistochemistry and immunoblotting revealed a striking increase of apoptosis in Bcl-xL-negative tumors. qRT-PCR and immunohistochemistry excluded changes in proliferative capacity and immune cell infiltration as reasons for the reduced tumor load and thereby identify apoptosis as key mechanism. Human CRC tissue was cultured ex vivo and treated with the small molecule compound ABT-737, which inhibits Bcl-xL and Bcl-2. Under ABT-737 treatment, the amount of apoptotic tumor cells significantly increased compared with controls, whereas proliferation levels remained unaltered. In summary, our findings identify Bcl-xL as a driver in colorectal tumorigenesis and cancer progression, making it a valuable target for clinical application.
publisher	Nature Publishing Group
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108319/
_version_	1613725934616051712

Bcl-xL is an oncogenic driver in colorectal cancer

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