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The apoptosis inhibitor Bcl-xL controls breast cancer cell migration through mitochondria-dependent reactive oxygen species production


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.

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Fig. 1: Bcl-xL protein levels in human breast epithelial cell lines.
Fig. 2: High bclx gene expression level is of poor prognosis in oestrogen receptor-positive patients.
Fig. 3: Bclx silencing impairs migration of mammary cancer cell lines.
Fig. 4: Bclx silencing inhibits the ability of 4T1cells to metastasize to the lung.
Fig. 5: Bcl-xL controls cell migration independently of its anti-apoptotic activity.
Fig. 6: Mitochondrial-, but not ER-targeted Bcl-xL, rescues cell migration.
Fig. 7: Mito-Bcl-xL forsters cell migration contrary to ER-Bcl-xL.
Fig. 8: Bcl-xL controls cell migration via its BH4 domain.
Fig. 9: Bclx silencing alters mitochondrial ATP generation.
Fig. 10: Cell motility alterations and drop in ROS production are closely correlated.
Fig. 11: Bclx silencing compromises calcium homeostasis.


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We would like to thank Stéphane Borel for technical assistance, Julien Prudent for critical reading of the manuscript, Brigitte Manship for manuscript editing, Isabelle Goddard for skilful technical assistance regarding studies in mice (LMT, Lyon), and CIQLE core facility (SFR Santé Lyon-Est) for videomicroscopy. This work was supported by AFM telethon (to GG, grant # 20269) and Fondation ARC to GG (grant # PGA1 RF20180206799) and JL (grant # PJA 20161204606).

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Correspondence to Ruth Rimokh or Germain Gillet.

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These authors contributed equally: Ruth Rimokh, Germain Gillet

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Bessou, M., Lopez, J., Gadet, R. et al. The apoptosis inhibitor Bcl-xL controls breast cancer cell migration through mitochondria-dependent reactive oxygen species production. Oncogene 39, 3056–3074 (2020).

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