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

被引:44
作者
Bessou, Margaux [1 ]
Lopez, Jonathan [1 ,2 ]
Gadet, Rudy [1 ]
Deygas, Mathieu [1 ,5 ]
Popgeorgiev, Nikolay [1 ]
Poncet, Delphine [1 ,2 ]
Nougarede, Adrien [1 ,6 ]
Billard, Pauline [1 ]
Mikaelian, Ivan [1 ]
Gonzalo, Philippe [1 ,3 ]
Rimokh, Ruth [1 ]
Gillet, Germain [1 ,4 ]
机构
[1] Univ Claude Bernard Lyon 1, Univ Lyon, Ctr Rech Cancerol Lyon, Ctr Leon Berard,INSERM 1052,CNRS 5286, F-69008 Lyon, France
[2] Hosp Civils Lyon, Ctr Hosp Lyon Sud, Ctr Biol Sud, Chemin Grand Revoyet, F-69495 Pierre Benite, France
[3] CHU St Etienne, Lab Biochim, F-42000 St Etienne, France
[4] Hosp Civils Lyon, Ctr Hosp Lyon Sud, Lab Anat & Cytol Pathol, Chemin Grand Revoyet, F-69495 Pierre Benite, France
[5] Inst Curie, CNRS, UMR144, 6 Rue Jean Calvin, F-75005 Paris, France
[6] CEA LETI, 17 Ave Martyrs, F-38000 Grenoble, France
关键词
ANION CHANNEL; ENDOPLASMIC-RETICULUM; CYTOCHROME-C; BH4; DOMAIN; BCL-X(L); FAMILY; CALCIUM; VDAC; METASTASIS; RELEASE;
D O I
10.1038/s41388-020-1212-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3056 / 3074
页数:19
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