气候变化领域集成服务门户(CCPortal): The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage

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DOI	10.1073/pnas.2112674118
	The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage
	De S.; Holvey-Bates E.G.; Mahen K.; Willard B.; Stark G.R.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:47
英文摘要	High expression of programmed death-ligand 1 (PD-L1) in cancer cells drives immune-independent, cell-intrinsic functions, leading to resistance to DNA-damaging therapies. We find that high expression of the ubiquitin E3 ligase FBXO22 sensitizes nonsmall cell lung cancer (NSCLC) cells to ionizing radiation (IR) and cisplatin, and that activation of FBXO22 by phosphorylation is necessary for this function. Importantly, FBXO22 activates PD-L1 ubiquitination and degradation, which in turn increases the sensitivity of NSCLC cells to DNA damage. Cyclin-dependent kinase 5 (CDK5), aberrantly active in cancer cells, plays a crucial role in increasing the expression of PD-L1 in medulloblastoma [R. D. Dorand et al., Science 353, 399-403 (2016)]. We show in NSCLC cells that inhibiting CDK5 or reducing its expression increases the level of FBXO22, decreases that of PD-L1, and increases the sensitivity of the cells to DNA damage. We conclude that FBXO22 is a substrate of CDK5, and that inhibiting CDK5 reduces PD-L1 indirectly by increasing FBXO22. Pairing inhibitors of CDK5 with immune checkpoint inhibitors may increase the efficacy of immune checkpoint blockade alone or in combination with DNA-damaging therapies. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	CDK5; FBXO22; Lung cancer; PD-L1
语种	英语
scopus关键词	cisplatin; cyclin dependent kinase 5; programmed death 1 ligand 1; ubiquitin E3 ligase FBXO22; ubiquitin protein ligase E3; unclassified drug; CD274 protein, human; CDK5 protein, human; cell receptor; cyclin dependent kinase 5; F box protein; FBXO22 protein, human; programmed death 1 ligand 1; ubiquitin; ubiquitin protein ligase; A-549 cell line; Article; Calu-1 cell line; cancer cell; cancer survival; controlled study; DNA damage; down regulation; enzyme activation; enzyme inhibition; enzyme phosphorylation; human; ionizing radiation; medulloblastoma; non small cell lung cancer; protein degradation; protein expression; protein function; sensitization; ubiquitination; upregulation; DNA damage; gene expression regulation; genetics; lung tumor; metabolism; phosphorylation; A549 Cells; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Cyclin-Dependent Kinase 5; DNA Damage; F-Box Proteins; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Medulloblastoma; Phosphorylation; Receptors, Cytoplasmic and Nuclear; Ubiquitin-Protein Ligases; Ubiquitination; Ubiquitins
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250974
作者单位	Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States; Proteomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States
推荐引用方式 GB/T 7714	De S.,Holvey-Bates E.G.,Mahen K.,et al. The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage[J],2021,118(47).
APA	De S.,Holvey-Bates E.G.,Mahen K.,Willard B.,&Stark G.R..(2021).The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage.Proceedings of the National Academy of Sciences of the United States of America,118(47).
MLA	De S.,et al."The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage".Proceedings of the National Academy of Sciences of the United States of America 118.47(2021).