Abstract
Mitophagy is a degradative pathway that mediates the degradation of the entire mitochondria, and defects in this process are implicated in many diseases including cancer. In mammals, mitophagy is mediated by BNIP3L (also known as NIX) that is a dual regulator of mitochondrial turnover and programmed cell death pathways. Acute myeloid leukemia (AML) cells with deficiency of BNIP3L are more sensitive to mitochondria-targeting drugs. But small molecular inhibitors for BNIP3L are currently not available. Some immunomodulatory drugs (IMiDs) have been proved by FDA for hematologic malignancies, however, the underlining molecular mechanisms are still elusive, which hindered the applications of BNIP3L inhibition for AML treatment. In this study we carried out MS-based quantitative proteomics analysis to identify the potential neosubstrates of a novel thalidomide derivative CC-885 in A549 cells. In total, we quantified 5029 proteins with 36 downregulated in CRBN+/+ cell after CC-885 administration. Bioinformatic analysis showed that macromitophagy pathway was enriched in the negative pathway after CC-885 treatment. We further found that CC-885 caused both dose- and time-dependent degradation of BNIP3L in CRBN+/+, but not CRBN−/− cell. Thus, our data uncover a novel role of CC-885 in the regulation of mitophagy by targeting BNIP3L for CRL4CRBN E3 ligase-dependent ubiquitination and degradation, suggesting that CC-885 could be used as a selective BNIP3L degradator for the further investigation. Furthermore, we demonstrated that CC-885 could enhance AML cell sensitivity to the mitochondria-targeting drug rotenone, suggesting that combining CC-885 and mitochondria-targeting drugs may be a therapeutic strategy for AML patients.
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Data availability
The proteomics data in this study have been uploaded to the iProx database (project ID: IPX0001589000).
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No. 81872888, No. 91753203, No. 81773018), the Natural Science Foundation of China for Innovation Research Group (No. 81821005), and the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (No. 2018ZX09711002-004).
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MJT and BL conceived the project and designed the experiments. BBH performed the proteomic experiments and data analysis with the help of MJT, GFX, and LHZ. BBH, XJL, XLJ, YXW, DZL, JL, DZ, YLC, YHX, and SKL carried out other experiments with the help of XHC, BL and YJD. BL and BBH wrote the manuscript, and MJT revised the manuscript.
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Hao, Bb., Li, Xj., Jia, Xl. et al. The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L. Acta Pharmacol Sin 41, 1246–1254 (2020). https://doi.org/10.1038/s41401-020-0367-9
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DOI: https://doi.org/10.1038/s41401-020-0367-9
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