The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L
| Autor: | Sangkyu Lee, Linhui Zhai, Xiaojing Li, Xiao-Hua Chen, Guofeng Xu, Jie Liu, Bin Liu, Duanzhuo Li, Yong-Hu Xu, Yuxing Wang, Die Zhang, Minjia Tan, Yulu Chen, Bingbing Hao, Xing-Long Jia, Yongjun Dang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Programmed cell death Ubiquitin-Protein Ligases Cell acute myeloid leukemia Mitochondrion Article BNIP3L 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Proto-Oncogene Proteins Rotenone Mitophagy medicine Humans Pharmacology (medical) Adaptor Proteins Signal Transducing CC-885 Pharmacology A549 cell Macromitophagy Chemistry Phenylurea Compounds Tumor Suppressor Proteins Cereblon Ubiquitination Membrane Proteins Myeloid leukemia Drug Synergism General Medicine immunomodulatory drugs (IMiDs) mitochondria-targeting drugs Thalidomide HEK293 Cells 030104 developmental biology medicine.anatomical_structure CRBN 030220 oncology & carcinogenesis Proteolysis Cancer research |
| Zdroj: | Acta Pharmacologica Sinica |
| ISSN: | 1745-7254 1671-4083 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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