BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer.
Details
Serval ID
serval:BIB_59DEDA1B732A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer.
Journal
Cell death and differentiation
ISSN
1476-5403 (Electronic)
ISSN-L
1350-9047
Publication state
Published
Issued date
12/2021
Peer-reviewed
Oui
Volume
28
Number
12
Pages
3282-3296
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Evasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival. We therefore hypothesized that a shift in antiapoptotic protein reliance occurs in ISCs as the disease progresses from normal to adenoma to carcinoma. By targeting antiapoptotic proteins with specific BH3 mimetics in organoid models of CRC progression, we found that BCL-2 is essential only during ISC transformation while MCL1 inhibition did not affect adenoma outgrowth. BCL-XL, on the other hand, was crucial for stem cell survival throughout the adenoma-to-carcinoma sequence. Furthermore, we identified that the limited window of BCL-2 reliance is a result of its downregulation by miR-17-5p, a microRNA that is upregulated upon APC-mutation driven transformation. Here we show that BCL-XL inhibition effectively impairs adenoma outgrowth in vivo and enhances the efficacy of chemotherapy. In line with this dependency, expression of BCL-XL, but not BCL-2 or MCL1, directly correlated to the outcome of chemotherapy-treated CRC patients. Our results provide insights to enable the rational use of BH3 mimetics in CRC management, particularly underlining the therapeutic potential of BCL-XL targeting mimetics in both early and late-stage disease.
Keywords
Adenoma/genetics, Adenoma/mortality, Adenoma/pathology, Animals, Apoptosis, Colorectal Neoplasms/genetics, Colorectal Neoplasms/mortality, Colorectal Neoplasms/pathology, Disease Progression, Female, Humans, Male, Mice, Survival Analysis, bcl-X Protein/genetics
Pubmed
Web of science
Open Access
Yes
Create date
28/06/2021 11:25
Last modification date
08/08/2024 6:34