Oncogene, 2020-04, Vol.39 (15), p.3056-3074
2020
Details
- Autor(en) / Beteiligte
- Titel
- The apoptosis inhibitor Bcl-xL controls breast cancer cell migration through mitochondria-dependent reactive oxygen species production
- Ist Teil von
- Oncogene, 2020-04, Vol.39 (15), p.3056-3074
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The Bcl-xL apoptosis inhibitor plays a major role in vertebrate development. In addition to its effect on apoptosis, Bcl-xL is also involved in cell migration and mitochondrial metabolism. These effects may favour the onset and dissemination of metastasis. However, the underlying molecular mechanisms remain to be fully understood. Here we focus on the control of cell migration by Bcl-xL in the context of breast cancer cells. We show that Bcl-xL silencing led to migration defects in Hs578T and MDA-MB231 cells. These defects were rescued by re-expressing mitochondria-addressed, but not endoplasmic reticulum-addressed, Bcl-xL. The use of BH3 mimetics, such as ABT-737 and WEHI-539 confirmed that the effect of Bcl-xL on migration did not depend on interactions with BH3-containing death accelerators such as Bax or BH3-only proteins. In contrast, the use of a BH4 peptide that disrupts the Bcl-xL/VDAC1 complex supports that Bcl-xL by acting on VDAC1 permeability contributes to cell migration through the promotion of reactive oxygen species production by the electron transport chain. Collectively our data highlight the key role of Bcl-xL at the interface between cell metabolism, cell death, and cell migration, thus exposing the VDAC1/Bcl-xL interaction as a promising target for anti-tumour therapy in the context of metastatic breast cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/s41388-020-1212-9Titel-ID: cdi_hal_primary_oai_HAL_hal_03094820v1
- Format
- –
- Schlagworte
- 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid - pharmacology, 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid - therapeutic use, Animals, Antineoplastic Agents - pharmacology, Antineoplastic Agents - therapeutic use, Apoptosis, Apoptosis - drug effects, Apoptosis - genetics, Bax protein, Bcl-x protein, bcl-X Protein - antagonists & inhibitors, bcl-X Protein - genetics, bcl-X Protein - metabolism, Biphenyl Compounds - pharmacology, Biphenyl Compounds - therapeutic use, Breast - pathology, Breast cancer, Breast Neoplasms - drug therapy, Breast Neoplasms - pathology, Care and treatment, Cell adhesion & migration, Cell death, Cell Line, Tumor, Cell migration, Cell Movement - drug effects, Cell Movement - genetics, Development and progression, Disease Models, Animal, Electron transport chain, Endoplasmic reticulum, Female, Gene expression, Gene Knockdown Techniques, Genetic aspects, Health aspects, Humans, Life Sciences, Lymphatic Metastasis - pathology, Metabolism, Metastases, Mitochondria, Mitochondria - drug effects, Mitochondria - metabolism, Molecular modelling, Neoplasm Invasiveness - genetics, Neoplasm Invasiveness - pathology, Neoplasm Invasiveness - prevention & control, Nitrophenols - pharmacology, Nitrophenols - therapeutic use, Oncogenes, Permeability, Piperazines - pharmacology, Piperazines - therapeutic use, Protein Binding - drug effects, Reactive oxygen species, Reactive Oxygen Species - metabolism, RNA, Small Interfering - metabolism, Sulfonamides - pharmacology, Sulfonamides - therapeutic use, Tumors, Voltage-Dependent Anion Channel 1 - antagonists & inhibitors, Voltage-Dependent Anion Channel 1 - metabolism, Xenograft Model Antitumor Assays, Zebrafish