Journal
AUTOPHAGY
Volume 11, Issue 3, Pages 452-459Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2015.1017191
Keywords
ABT-737; apoptosis; autophagy; BAX; BAK1; BCL2; BECN1 (Beclin 1); ACTB; actin; Baf A1; bafilomycin A(1); BAK1; BCL2-antagonist; killer 1; BAX; BCL2-associated X protein; BCL2; B-cell CLL; lymphoma 2; BECN1; Beclin 1; autophagy-related; 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
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Funding
- CPRIT [RP120718-P1]
- NIH [R01CA109618, U19AI109725]
- Ligue contre le Cancer
- Agence National de la Recherche (ANR)
- Association pour la recherche sur le cancer (ARC)
- Canceropole Ile-de-France
- Institut National du Cancer (INCa)
- Fondation Bettencourt-Schueller
- Fondation de France
- Fondation pour la Recherche Medicale (FRM)
- European Commission (ArtForce)
- European Research Council (ERC)
- LabEx Immuno-Oncology
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- Paris Alliance of Cancer Research Institutes (PACRI)
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Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-X-L 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-X-L 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.
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