Investigating the mechanism of tricyclic decyl benzoxazole -induced apoptosis in liver Cancer cells through p300-mediated FOXO3 activation

• Published in: Cellular signalling 2024-09, Vol.121, p.111280, Article 111280
• Main Authors: Tian, Shuhong, Zhong, Keyan, Yang, Zhaoxin, Fu, Jian, Cai, Yangbo, Xiao, Min
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Apoptosis; Apoptosis - drug effects; Benzoxazoles - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; E1A-Associated p300 Protein - metabolism; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; FOXO3 acetylation; Gene Expression Regulation, Neoplastic - drug effects; Humans; Liver cancer; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; p300; Phosphorylation - drug effects; Signal Transduction - drug effects; TDB
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2024.111280

To investigate whether tricyclic decylbenzoxazole (TDB) regulates liver cancer cell proliferation and apoptosis through p300-mediated FOXO acetylation. Sequencing, adenovirus, and lentivirus transfection were performed in human liver cancer cell line SMMC-7721 and apoptosis was detected by Tunel, Hoechst, and flow cytometry. TEM for mitochondrial morphology, MTT for cell proliferation ability, Western blot, and PCR were used to detect protein levels and mRNA changes. Sequencing analysis and cell experiments confirmed that TDB can promote the up-regulation of FOXO3 expression. TDB induced FOXO3 up-regulation in a dose-dependent manner, promoted the expression of p300 and Bim, and enhanced the acetylation and dephosphorylation of FOXO3, thus promoting apoptosis. p300 promotes apoptosis of cancer cells through Bim and other proteins, while HAT enhances the phosphorylation of FOXO3 and inhibits apoptosis. Overexpression of FOXO3 can increase the expression of exo-apoptotic pathways (FasL, TRAIL), endo-apoptotic pathways (Bim), and acetylation at the protein level and inhibit cell proliferation and apoptotic ability, while FOXO3 silencing or p300 mutation can partially reverse apoptosis. In tumor tissues with overexpression of FOXO3, TDB intervention can further increase the expression of p53 and caspase-9 proteins in tumor cells, resulting in loss of mitochondrial membrane integrity during apoptosis, the release of cytoplasm during signal transduction, activation of caspase-9 and synergistic inhibition of growth. TDB induces proliferation inhibition and promotes apoptosis of SMMC-7721 cells by activating p300-mediated FOXO3 acetylation. •FOXO3 was up-regulated after TDB intervention in hepatocellular carcinoma.•FOXO3 is a candidate therapeutic target for TDB to inhibit value-added and induce apoptosis.•Overexpression of FOXO3 significantly inhibited TDB proliferation and induced apoptosis in vivo/in vitro.