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.
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.