Zeng Chao, Zhang Zhixuan, Luo Wei, Wang Liyang, Zhou Hang, Nie Chunlai
Department of Gastroenterology, The Third People's Hospital of Chengdu, Chengdu, 610031, PR China.
Department of Chemotherapy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, PR China.
Exp Cell Res. 2022 May 15;414(2):113105. doi: 10.1016/j.yexcr.2022.113105. Epub 2022 Mar 17.
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.
ABT-199是一种Bcl-2蛋白的特异性抑制剂，广泛应用于血液肿瘤的临床试验，很少应用于实体瘤的研究。在本研究中，我们以Bax/Bak双敲除（KO）和敲低（KD）细胞为模型，发现ABT-199引发自噬性细胞死亡，且不依赖于Bax和Bak。ABT-199引发依赖于Beclin-1的自噬，进而导致细胞死亡。此外，在经ABT-199处理的细胞中，失活的Akt通过改变Beclin-1的磷酸化状态，从14-3-3蛋白上释放Beclin-1。此外，JNK通过磷酸化14-3-3蛋白拮抗Akt在Beclin-1介导的自噬中的功能。磷酸化的14-3-3与Beclin-1的相互作用减弱。因此，ABT-199激活JNK-Akt-14-3-3信号通路，介导Bax/Bak KO和KD细胞依赖于Beclin-1的自噬性死亡。这些发现可能会将ABT-199的治疗应用扩展到结肠癌，特别是凋亡缺陷型肿瘤。
