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The mtDNA-STING pathway plays an important role in both navitoclax- and S63845-induced autophagy and enhances cell death

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Abstract

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/BCLXL/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.

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This study includes no data deposited in external repositories. All the raw data reported in this paper will be shared by the lead contact upon request.

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Acknowledgements

We thank for Dr. Scott Kaufmann from Mayo Clinic for the cell lines, plasmids and helpful discussions. We thank for Dr. Shengbing Huang from Mayo Clinc for plasmids.

Funding

This work is supported by the National Natural Science Foundation of China (No. 31970701), the Anhui Provincial Key R&D Program (No. 202104a07020007), and the co-operative grants from Anhui Medical University and Center of Medical Physics and Technology (No. LHJJ202006, No. LHJJ202007).

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Authors and Affiliations

  1. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health & Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, Anhui, China

    Jia Jia, Mengqing Li, Yunjian Li & Haiming Dai

  2. University of Science and Technology of China, Hefei, 230026, Anhui, China

    Jia Jia

  3. Department of Pathology and Laboratory Medicine, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, 230031, China

    Jia Jia, Mengqing Li, Yunjian Li & Haiming Dai

  4. Department of Urology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Jun Xiao

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Contributions

Conceptualization, H.D. and J.X; Investigation, J.J., M.L., Y.L. and H.D.; Writing, H.D., J.X., and J.J.; Review & Editing, H.D., J.J., M.L., Y.L., and J.X.

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Jia, J., Li, M., Li, Y. et al. The mtDNA-STING pathway plays an important role in both navitoclax- and S63845-induced autophagy and enhances cell death. Cell Biol Toxicol 39, 2821–2839 (2023). https://doi.org/10.1007/s10565-023-09804-x

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