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Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression

福克斯M1 癌症研究 癌变 污渍 化学 癌症 细胞凋亡 生物 细胞周期 生物化学 基因 遗传学
作者
Kun Wang,Xiaoyong Dai,Albert Cheung Hoi Yu,Chunyan Feng,Kewei Liu,Laiqiang Huang
出处
期刊:Journal of Experimental & Clinical Cancer Research [Springer Nature]
卷期号:41 (1) 被引量:36
标识
DOI:10.1186/s13046-022-02483-2
摘要

Peptide proteolysis-targeting chimeras (p-PROTACs) with advantages of high specificity and low toxicity have emerged as a powerful technology of targeted protein degradation for biomedical applications. FOXM1, a proliferation-associated transcription factor, is overexpressed in a variety of human tumors as a key driver of tumorigenesis and cancer progression, and is a potential anticancer therapeutic target. However, FOXM1-targeting p-PROTACs has not been researched.Here, we first analyzed the expression of FOXM1, GLUT1 and PD-L1 in liver cancer through database and clinical samples of patients. FOXM1-targeting peptides, selected by screening phage display library, are verified its targeting effect by immunofluorescence and CCK-8 test. The novel p-PROTAC degrader of FOXM1 is chemically synthesis, named FOXM1-PROTAC, by linking a FOXM1-binding antagonistic peptide, with the E3 ubiquitin ligase recruitment ligand Pomalidomide and with the cell membrane penetrating peptide TAT. Its degradation effect on FOXM1 was detected by Western blotting, qPCR, and we verified its effect on the behavior of cancer cells by flow cytometry, scratch assay, and Transwell in vitro. The tumor xenografted mice model was used for evaluating FOXM1-PROTAC therapeutic response in vivo. Finally, we detected the expression of GLUT1 and PD-L1 after FOXM1-PROTAC degraded FOXM1 by using Western Blotting and hippocampal detectors and dual immunofluorescence.We found that the novel FOXM1-PROTAC efficiently entered cells and induced degradation of FOXM1 protein, which strongly inhibits viability as well as migration and invasion in various cancer cell lines, and suppressed tumor growth in HepG2 and MDA-MB-231 cells xenograft mouse models, without detected toxicity in normal tissues. Meanwhile, FOXM1-PROTAC decreased the cancer cells glucose metabolism via downregulating the protein expression levels of glucose transporter GLUT1 and the immune checkpoint PD-L1, which suggests involvement of FOXM1 in cancer cell metabolism and immune regulation.Our results indicate that biologically targeted degradation of FOXM1 is an attractive therapeutic strategy, and antagonist peptide-containing FOXM1-PROTACs as both degrader and inhibitor of FOXM1 could be developed as a safe and promising drug for FOXM1-overexpressed cancer therapy.
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