PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Scherr, A.L.* ; Gdynia, G.* ; Salou, M.* ; Radhakrishnan, P.* ; Duglova, K.* ; Heller, A.* ; Keim, S.* ; Kautz, N.* ; Jassowicz, A.* ; Elssner, C.* ; He, Y.W.* ; Jaeger, D.* ; Heikenwälder, M. ; Schneider, M.* ; Weber, A.* ; Roth, W.* ; Schulze-Bergkamen, H.* ; Koehler, B.C.*

Bcl-xL is an oncogenic driver in colorectal cancer.

Cell Death Dis. 7:e2342 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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-xL(IEC-KO)). If challenged in an inflammation-driven tumor model, Bcl-xL(IEC-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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
5.378
0.000
52
64
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Keywords Bcl-x; Apoptosis Resistance; Cell-death; Expression; Protein; Family; Carcinoma; Overexpression; Chemotherapy; Progression
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 2041-4889
e-ISSN 2041-4889
Journal Cell Death & Disease
Quellenangaben Volume: 7, Issue: 8, Pages: , Article Number: e2342 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
PSP Element(s) G-551600-001
G-502700-001
PubMed ID 27537525
DOI 10.1038/cddis.2016.233
WOS ID WOS:000382077800005
Erfassungsdatum 2016-09-06
[➜Report correction]