Paradoxical implication of BAX/BAK in the persistence of tetraploid cells.

Autor: Deng J; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France., Gutiérrez LG; Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid - CSIC, Valladolid, Spain., Stoll G; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France., Motiño O; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France., Martins I; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France., Núñez L; Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid - CSIC, Valladolid, Spain., Bravo-San Pedro JM; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.; Facultad de Medicina, Departamento de Fisiología, Universidad Complutense de Madrid, Madrid, Spain., Humeau J; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC, Canada, H3C 3J7.; Department of Medicine, Université de Montréal, Montreal, QC, Canada, H3C 3J7., Bordenave C; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France., Pan J; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France., Fohrer-Ting H; Centre de Recherche des Cordeliers, Center for Histology, Cell Imaging and Cytometry (CHIC), Sorbonne Université, Inserm, Université de Paris, F-75006, Paris, France., Souquere S; AMMICA-UMS3655, Gustave Roussy, 94800, Villejuif, France., Pierron G; CNRS, UMR9196, Gustave Roussy Cancer Campus, Villejuif, France., Hetz C; Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, 8380453, Chile.; Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, 7800003, Chile.; The Buck Institute for Research in Aging, Novato, CA, 94945, USA., Villalobos C; Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid - CSIC, Valladolid, Spain. carlosv@ibgm.uva.es., Kroemer G; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France. kroemer@orange.fr.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. kroemer@orange.fr.; Pôle de Biologie, Hopitâl Européen George Pompidou, AP-HP, Paris, France. kroemer@orange.fr., Senovilla L; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Equipe 11 Labellisée par la Ligue Contre le Cancer, F-75006, Paris, France. laurasenovilla@hotmail.com.; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France. laurasenovilla@hotmail.com.; Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid - CSIC, Valladolid, Spain. laurasenovilla@hotmail.com.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2021 Nov 01; Vol. 12 (11), pp. 1039. Date of Electronic Publication: 2021 Nov 01.
DOI: 10.1038/s41419-021-04321-3
Abstrakt: Pro-apoptotic multi-domain proteins of the BCL2 family such as BAX and BAK are well known for their important role in the induction of mitochondrial outer membrane permeabilization (MOMP), which is the rate-limiting step of the intrinsic pathway of apoptosis. Human or mouse cells lacking both BAX and BAK (due to a double knockout, DKO) are notoriously resistant to MOMP and cell death induction. Here we report the surprising finding that BAX/BAK DKO cells proliferate less than control cells expressing both BAX and BAK (or either BAX or BAK) when they are driven into tetraploidy by transient exposure to the microtubule inhibitor nocodazole. Mechanistically, in contrast to their BAX/BAK-sufficient controls, tetraploid DKO cells activate a senescent program, as indicated by the overexpression of several cyclin-dependent kinase inhibitors and the activation of β-galactosidase. Moreover, DKO cells manifest alterations in ionomycin-mobilizable endoplasmic reticulum (ER) Ca 2+ stores and store-operated Ca 2+ entry that are affected by tetraploidization. DKO cells manifested reduced expression of endogenous sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (Serca2a) and transfection-enforced reintroduction of Serca2a, or reintroduction of an ER-targeted variant of BAK into DKO cells reestablished the same pattern of Ca 2+ fluxes as observed in BAX/BAK-sufficient control cells. Serca2a reexpression and ER-targeted BAK also abolished the tetraploidy-induced senescence of DKO cells, placing ER Ca 2+ fluxes downstream of the regulation of senescence by BAX/BAK. In conclusion, it appears that BAX/BAK prevent the induction of a tetraploidization-associated senescence program. Speculatively, this may contribute to the low incidence of cancers in BAX/BAK DKO mice and explain why human cancers rarely lose the expression of both BAX and BAK.
(© 2021. The Author(s).)
Databáze: MEDLINE
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