JNK initiates Beclin-1 dependent autophagic cell death against Akt activation.

ABT-199, a specific inhibitor of the Bcl-2 protein, is widely used in clinical trials for hematological tumors and rarely applied to the research of solid tumors. In this study, we used Bax/Bak double knockout (KO) and knockdown (KD) cells as the model and found that ABT-199 initiated autophagic cell death independent of Bax and Bak. ABT-199 initiated Beclin-1-dependent autophagy, which led to cell death. Furthermore, inactivated Akt released Beclin-1 from the 14-3-3 protein through a change in the phosphorylation state of Beclin-1 in ABT-199-treated cells. Moreover, JNK antagonized the function of Akt in Beclin-1-mediated autophagy by phosphorylating the 14-3-3 protein. Phosphorylated 14-3-3 exhibited a decreased interaction with Beclin-1. Therefore, ABT-199 activated the JNK-Akt-14-3-3 signaling pathway to mediate the Beclin-1-dependent autophagic death of Bax/Bak KO and KD cells. These findings may extend the therapeutic application of ABT-199 to colon cancer, particularly apoptosis-deficient tumors.