The apoptosis inhibitor Bcl-xL controls breast cancer cell migration through mitochondria-dependent reactive oxygen species production.
Margaux BessouJonathan LopezRudy GadetMathieu DeygasNikolay PopgeorgievDelphine PoncetAdrien NougarèdePauline BillardIvan MikaelianPhilippe GonzaloRuth RimokhGermain GilletPublished in: Oncogene (2020)
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.
Keyphrases
- cell migration
- cell death
- cell cycle arrest
- reactive oxygen species
- oxidative stress
- breast cancer cells
- endoplasmic reticulum
- endoplasmic reticulum stress
- magnetic resonance
- induced apoptosis
- signaling pathway
- cell proliferation
- stem cells
- magnetic resonance imaging
- computed tomography
- pi k akt
- machine learning
- bone marrow
- single cell