title: BAX and BAK1 are dispensable for ABT-737-induced dissociation of the BCL2-BECN1 complex and autophagy.
abstract: Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-XL is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-XL may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT-737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members.
authors.affiliation: a Equipe 11 labellisée pas la Ligue Nationale contre le Cancer ; Center de Recherche des Cordeliers ; Paris , France.
authors.forename: Jose Manuel Bravo-San
authors.initials: JM
authors.lastname: Pedro
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wei
authors.forename: Valentina
authors.initials: V
authors.lastname: Sica
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Maiuri
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Zou
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D001713:Biphenyl Compounds / Q000737:chemistry*; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D045325:HCT116 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009596:Nitrophenols / Q000737:chemistry*; D010446:Peptide Fragments; D010879:Piperazines / Q000737:chemistry; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C494772:BAK1 protein, human; C494826:BAX protein, human; C000595707:BCL2 protein, human; C491997:BECN1 protein, human; C494773:Bak1 protein, mouse; C474007:Bax protein (53-86); C494827:Bax protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse
keywords: ABT-737; ACTB, actin, β; BAK1; BAK1, BCL2-antagonist/killer 1; BAX; BAX, BCL2-associated X protein; BCL2; BCL2, B-cell CLL/lymphoma 2; BECN1 (Beclin 1); BECN1, Beclin 1, autophagy-related; Baf A1, bafilomycin A1; DKO, double-knockout; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HBSS, Hanks’ balanced salt solution; HRP, horseradish peroxidase; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MCL1, myeloid cell leukemia 1; MEFs, mouse embryonic fibroblasts; MTOR, mechanistic target of rapamycin; PBS, phosphate-buffered saline; SQSTM1, sequestosome 1; STS, staurosporine; WT, wild type; apoptosis; autophagy