PMID- 38183094 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240108 IS - 1749-8546 (Print) IS - 1749-8546 (Electronic) IS - 1749-8546 (Linking) VI - 19 IP - 1 DP - 2024 Jan 5 TI - Interfering with the AKT/mTOR/STAT3/ID1 signaling axis with usenamine A restrains the proliferative and invasive potential of human hepatocellular carcinoma cells. PG - 4 LID - 10.1186/s13020-023-00875-w [doi] LID - 4 AB - BACKGROUND: Usenamine A, a novel natural compound initially isolated from the lichen Usnea longissima, has exhibited promising efficacy against hepatoma in prior investigation. Nevertheless, the underlying mechanisms responsible for its antihepatoma effects remain unclear. Furthermore, the role of the AKT/mechanistic target of the rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3)/inhibitor of differentiation/DNA binding 1 (ID1) signaling axis in hepatocellular carcinoma (HCC), and the potential anti-HCC effects of drugs targeting this pathway are not well understood. METHODS: CCK-8 assay was used to investigate the effects of usenamine A on the proliferation of human HCC cells. Moreover, the effects of usenamine A on the invasion ability of human HCC cells were evaluated by transwell assay. In addition, expression profiling analysis, quantitative real-time PCR, immunoblotting, immunohistochemistry (IHC) analysis, RNAi, immunoprecipitation, and chromatin immunoprecipitation (ChIP) assay were used to explore the effects of usenamine A on the newly identified AKT/mTOR/STAT3/ID1 signaling axis in human HCC cells. RESULTS: Usenamine A inhibited the proliferation and invasion of human HCC cell lines (HepG2 and SK-HEP-1). Through the analysis of gene expression profiling, we identified that usenamine A suppressed the expression of ID1 in human HCC cells. Furthermore, immunoprecipitation experiments revealed that usenamine A facilitated the degradation of the ID1 protein via the ubiquitin-proteasome pathway. Moreover, usenamine A inhibited the activity of STAT3 in human HCC cells. ChIP analysis demonstrated that STAT3 positively regulated ID1 expression at the transcriptional level in human HCC cells. The STAT3/ID1 axis played a role in mediating the anti-proliferative and anti-invasive impacts of usenamine A on human HCC cells. Additionally, usenamine A suppressed the STAT3/ID1 axis through AKT/mTOR signaling in human HCC cells. CONCLUSION: Usenamine A displayed robust anti-HCC potential, partly attributed to its capacity to downregulate the AKT/mTOR/STAT3/ID1 signaling pathway and promote ubiquitin-proteasome-mediated ID1 degradation. Usenamine A has the potential to be developed as a therapeutic agent for HCC cases characterized by abnormal AKT/mTOR/STAT3/ID1 signaling, and targeting the AKT/mTOR/STAT3 signaling pathway may be a viable option for treating patients with HCC exhibiting elevated ID1 expression. CI - (c) 2024. The Author(s). FAU - Yang, Ailin AU - Yang A AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. AD - School of Pharmacy, Binzhou Medical University, Yantai, 264003, China. FAU - Huang, Huiming AU - Huang H AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Xie, Jinxin AU - Xie J AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Tian, Yingying AU - Tian Y AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Wang, Longyan AU - Wang L AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Liu, Dongxiao AU - Liu D AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Wei, Xuejiao AU - Wei X AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Tan, Peng AU - Tan P AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Chai, Xingyun AU - Chai X AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Zha, Xiaojun AU - Zha X AD - Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China. FAU - Tu, Pengfei AU - Tu P AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. FAU - Hu, Zhongdong AU - Hu Z AUID- ORCID: 0000-0003-4849-3353 AD - Modern Research Center for Traditional Chinese Medicine, Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North 3rd Ring East Road, Chaoyang District, Beijing, 100029, People's Republic of China. zdhu@bucm.edu.cn. LA - eng GR - 81873044/National Natural Science Foundation of China/ GR - 82074072/National Natural Science Foundation of China/ GR - 82204693/National Natural Science Foundation of China/ GR - Z191100001119083/Beijing Nova Program of Science and Technology/ GR - 2023-JYB-JBQN-051/Fundamental Research Funds for the Central Universities/ GR - JZPY202206/Talent Cultivation Project of Beijing University of Chinese Medicine/ PT - Journal Article DEP - 20240105 PL - England TA - Chin Med JT - Chinese medicine JID - 101265109 PMC - PMC10770941 OTO - NOTNLM OT - AKT/mTOR/STAT3/ID1 axis OT - Hepatocellular carcinoma OT - Invasion OT - Proliferation OT - Usenamine A COIS- The authors declare that they have no competing interests. EDAT- 2024/01/06 10:41 MHDA- 2024/01/06 10:42 PMCR- 2024/01/05 CRDT- 2024/01/05 23:48 PHST- 2023/09/09 00:00 [received] PHST- 2023/12/29 00:00 [accepted] PHST- 2024/01/06 10:42 [medline] PHST- 2024/01/06 10:41 [pubmed] PHST- 2024/01/05 23:48 [entrez] PHST- 2024/01/05 00:00 [pmc-release] AID - 10.1186/s13020-023-00875-w [pii] AID - 875 [pii] AID - 10.1186/s13020-023-00875-w [doi] PST - epublish SO - Chin Med. 2024 Jan 5;19(1):4. doi: 10.1186/s13020-023-00875-w.