PuSH - Publication Server of Helmholtz Zentrum München

Keitel, U.* ; Scheel, A.* ; Thomale, J.* ; Halpape, R.* ; Kaulfuß, S.* ; Scheel, C. ; Dobbelstein, M.*

Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation.

Oncotarget 5, 11778-11791 (2014)
Publ. Version/Full Text DOI PMC
Free by publisher
Creative Commons Lizenzvertrag
The transition from an epithelial to a mesenchymal phenotype (EMT) confers increased invasiveness and clonogenic potential to tumor cells. We used a breast epithelium-derived cell culture model to evaluate the impact of EMT on the cellular sensitivity towards chemotherapeutics and apoptotic stimuli. Cells that had passed through an EMT acquired resistance towards chemotherapeutics and death ligands. Mechanistically, we found that the levels of the apoptosis inhibitor Bcl-xL were strongly enhanced in mesenchymal versus epithelial cells, whereas the pro-apoptotic proteins Bim and Puma were diminished. Clinical samples from breast cancer showed enhanced Bcl-xL staining in cells that had dispersed into the desmoplastic stroma, as compared to cells that were part of large tumor cell aggregates, suggesting increased Bcl-xL expression when cells invade the stroma. Bcl-xL was necessary for apoptotic resistance in mesenchymal cells, and its expression was sufficient to confer such resistance to epithelial cells. To antagonize Bcl-xL, BH3-mimetics were used. They successfully interfered with the proliferation and survival of mesenchymal cells, and also inhibited the growth of xenograft tumors raised from the mesenchymal subpopulation. We conclude that enhanced Bcl-xL levels confer resistance to cells upon EMT, and that Bcl-xL represents a promising target for therapy directed against invasive cancer cells.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bcl-xl ; Chemo-resistance ; Epithelial-mesenchymal Transition ; Apoptosis ; Bh3-mimetic; Stem-cells; Carcinoma Cells; Transition; Proteins; Progression; Paclitaxel; Plasticity; Phenotype; Apoptosis; Autophagy
ISSN (print) / ISBN 1949-2553
e-ISSN 1949-2553
Journal OncoTarget
Quellenangaben Volume: 5, Issue: 23, Pages: 11778-11791 Article Number: , Supplement: ,
Publisher Impact Journals LLC
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)