Targeting BCL2 family proteins to induce cancer cell death has been successful in the treatment of cancer. BH3 mimetics such as ABT-737 not only induce cell death, but also activate autophagy. The molecular mechanism by which the BH3 mimetics induce autophagy is still controversial. In this study, we show that the BCL2/BCLX_L/BCLw inhibitor navitoclax and the MCL1 inhibitor S63845 induce both apoptosis and autophagy in mouse embryonic fibroblasts (MEFs) and leukemia cell lines, while autophagy induced by navticlax and S63845 in leukemia cell lines requires the inhibition of caspase activities. Further experiments demonstrate that the autophagy induced by navitoclax or S63845 does not depend on Beclin 1, but downstream of Bax/Bak. Moreover, both navitoclax and S63845 treatment induce mtDNA release in MEFs, which activates STING and thereby induces autophagy, while STING KO inhibits both navitoclax- and S63845-induced autophagy. Furthermore, STING KO diminishes navitoclax- or S63845-induced apoptosis, suggesting that STING activation enhances rather than inhibits apoptosis. Thus, our findings provide new insights into the regulations of navitoclax- or S63845-induced autophagy and cell death.

靶向 BCL2 家族蛋白以诱导癌细胞死亡已成功治疗癌症。BH3 模拟物如 ABT-737 不仅会诱导细胞死亡，还会激活自噬。BH3 模拟物诱导自噬的分子机制仍存在争议。在这项研究中，我们表明 BCL2/BCLX _L/BCLw 抑制剂 navitoclax 和 MCL1 抑制剂 S63845 在小鼠胚胎成纤维细胞 (MEF) 和白血病细胞系中诱导细胞凋亡和自噬，而在白血病细胞系中由 navticlax 和 S63845 诱导的自噬需要抑制 caspase 活性。进一步的实验表明，navitoclax 或 S63845 诱导的自噬不依赖于 Beclin 1，而是 Bax/Bak 的下游。此外，navitoclax 和 S63845 处理均诱导 MEF 中的 mtDNA 释放，从而激活 STING 从而诱导自噬，而 STING KO 抑制 navitoclax 和 S63845 诱导的自噬。此外，STING KO 减少 navitoclax 或 S63845 诱导的细胞凋亡，表明 STING 激活增强而不是抑制细胞凋亡。因此，