PAI-1 plays significant roles in cancer occurrence, relapse and multidrug resistance and is highly expressed in tumours. ACT001, which is currently in phase I clinical trials for the treatment of glioblastoma (GBM). However, the detailed molecular mechanism of ACT001 is still unclear. In this study, we investigated the effects of ACT001 on glioma cell proliferation and clarified its mechanism. We discovered that PAI-1 was the direct target of ACT001 by a cellular thermal shift assay. Then, the interaction between ACT001 and PAI-1 was verified by Biacore assays, thermal stability assays and ACT001 probe assays. Furthermore, from the proteomic analysis, we found that ACT001 directly binds PAI-1 to inhibit the PI3K/AKT pathway, which induces the inhibition of glioma cell proliferation, invasion and migration. Moreover, the combination of ACT001 and cisplatin showed a synergistic effect on the inhibition of glioma in vitro and in vivo. In conclusion, our findings demonstrate that PAI-1 is a new target of ACT001, the inhibition of PAI-1 induces glioma inhibition, and ACT001 has a synergistic effect with cisplatin through the inhibition of the PAI-1/PI3K/AKT pathway.

Background and Purpose: The role of the cartilage oligomeric matrix protein (COMP) in epithelial-mesenchymal transition (EMT) in tumor progression has been studied, but its exact regulatory mechanism remains unknown. Methods: The interaction between COMP and the actin-binding protein transgelin (TAGLN) was identified by interaction protein prediction and co-immunoprecipitation and verified through the stochastic optical reconstruction microscopy (STORM) and duolink experiments. Western blot and immunofluorescence analyses were conducted to detect the changes in EMT-related markers after COMP overexpression and knockdown. Molecular docking and Biacore of the interaction interface of COMP/TAGLN revealed that Chrysin directly targeted COMP. The promotion of COMP and the Chrysin inhibition of EMT were detected through the cell migration, invasion, apoptosis, and xenotransplantation of nude mice. Results: COMP interacts with TAGLN in EMT in colorectal cancer to regulate cytoskeletal remodeling and promote malignant progression. COMP is highly expressed in highly malignant colorectal cancer and positively correlated with TAGLN expression. COMP knockdown can inhibit colorectal cancer metastasis and invasion, whereas COMP overexpression promotes EMT in colorectal cancer. Through virtual screening of the protein interaction interface, Chrysin, a flavonoid compound extracted from Oroxylum indicum , was found to have the highest docking score to the COMP/TAGLN complex. Chrysin inhibited COMP, thereby preventing EMT and the malignant progression of colorectal cancer. Conclusions: This study illustrated the role of COMP in EMT and suggested that COMP/TAGLN may be a potential tumor therapeutic target. Chrysin exhibits obvious antitumor effects. This work provides a preliminary antitumor therapy to target COMP or its interaction protein to inhibit EMT.

Background: Glioma accounts for a large proportion of cancer, and an effective treatment for this disease is still lacking because of the absence of specific driver molecules. Current challenges in the treatment of glioma are the accurate and timely diagnosis of brain glioma and targeted treatment plans. To investigate the diagnostic biomarkers and prospective role of miRNAs in the tumorigenesis and progression of glioma, we analyzed the expression of miRNAs and key genes in glioma based on The Cancer Genome Atlas database. Methods: Of the 701 cases that were downloaded, five were normal and 696 were glioma. Then, 1626 differentially expressed genes were identified, and 173 aberrantly expressed miRNAs were calculated by edgeR. GO and KEGG pathway enrichment analyses were performed using Cytoscape software. A coexpression network was built by weighted correlation network analysis (WGCNA). A cell scratch test and transwell, cell apoptosis and cell cycle assays were performed to validate the function of hsa-let-7b-5p. Results: Based on crosstalk genes in the KEGG, PPI network, and WGCNA analyses, PLK1, CCNA2, cyclin B2 (CCNB2), and AURKA were screened as candidate diagnostic marker genes. The survival analysis revealed that high mRNA expression of PLK1, CCNA2, and AURKA was significantly associated with poor overall survival. Furthermore, hsalet-7b-5p was identified as a core miRNA in the regulation of candidate genes involved in glioma development. We confirmed that hsa-let-7b-5p could inhibit the migration, invasion, and cell cycle of glioma cells. Conclusions: This study provides four potential biomarkers for the diagnosis of glioma, offers a potential explanation of its pathogenesis, and proposes hsa-let-7b-5p as a therapeutic target.

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Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of the germacrane ring (24). The synthetic strategy features a selective aldol reaction between β,γ-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular α-alkylation of sulfone 21 to construct a 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogues, such as trifluoromethylated analogues 32 and 45. Analogues 32 and 45 maintained high activities against a series of cancer cell lines compared to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media compared with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes.