Dual inhibition of MYC and SLC39A10 by a novel natural product STAT3 inhibitor derived from Chaetomium globosum suppresses tumor growth and metastasis in gastric cancer. (March 2023)

• Record Type: Journal Article
• Authors: Guan, Xiaoqing; Yang, Jing; Wang, Weiyi; Zhao, Bing; Hu, Shiyu; Yu, Dehua; Yuan, Li; Shi, Yunfu; Xu, Jingli; Dong, Jinyun; Wang, Jinxin; Cheng, Xiang-Dong; Qin, Jiang-Jiang
• Is Part Of: Pharmacological research. Volume 189(2023)
• Publication Date: 2023-03
• Subjects: XYA-2 (PubChem CID: 156012778) -- C188–9 (PubChem CID: 1324494); STAT3 signal transducer and activator of transcription 3 -- PDX patient-derived xenograft -- FBS fetal bovine serum -- SPR surface plasmon resonance -- TMT tandem mass tag -- GO gene ontology -- KEGG kyoto encyclopedia of genes and genomes -- GSEA gene set enrichment analysis -- CCK8 cell counting kit 8 -- H&E hematoxylin and eosin -- IHC immunohistochemistry; Dual inhibition -- MYC -- SLC39A10 -- STAT3 inhibitor -- Gastric cancer; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2023.106703
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Gastric cancer remains one of the most common deadly diseases and lacks effective targeted therapies. In the present study, we confirmed that the signal transducer and activator of transcription 3 (STAT3) is highly expressed and associated with a poor prognosis in gastric cancer. We further identified a novel natural product inhibitor of STAT3, termed XYA-2, which interacts specifically with the SH2 domain of STAT3 ( K d = 3.29 μM) and inhibits IL-6-induced STAT3 phosphorylation at Tyr705 and nuclear translocation. XYA-2 inhibited the viability of seven human gastric cancer cell lines with 72-h IC50 values ranging from 0.5 to 0.7 μΜ. XYA-2 at 1 μΜ inhibited the colony formation and migration ability of MGC803 (72.6% and 67.6%, respectively) and MKN28 (78.5% and 96.6%, respectively) cells. In the in vivo studies, intraperitoneal administration of XYA-2 (10 mg/kg/day, 7 days/week) significantly suppressed 59.8% and 88.8% tumor growth in the MKN28-derived xenograft mouse model and MGC803-derived orthotopic mouse model, respectively. Similar results were obtained in a patient-derived xenograft (PDX) mouse model. Moreover, XYA-2 treatment extended the survival of mice bearing PDX tumors. The molecular mechanism studies based on transcriptomics and proteomics analyses indicated that XYA-2 might exert its anticancer activity by synergistically inhibiting the expression of MYC and SLC39A10, two downstream genes of STAT3 in vitro and in vivo . Together, these findings suggested that XYA-2 may be a potent STAT3 inhibitor for treating gastric cancer, and dual inhibition of MYC and SLC39A10 may be an effective therapeutic strategy for STAT3-activated cancer. Graphical Abstract: ga1