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  2. 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

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

  • Pharmacol Res. 2023 Feb 17;189:106703. doi: 10.1016/j.phrs.2023.106703.
Xiaoqing Guan 1 Jing Yang 2 Weiyi Wang 3 Bing Zhao 2 Shiyu Hu 2 Dehua Yu 2 Li Yuan 1 Yunfu Shi 2 Jingli Xu 2 Jinyun Dong 1 Jinxin Wang 4 Xiang-Dong Cheng 5 Jiang-Jiang Qin 6
Affiliations

Affiliations

  • 1 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 2 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 3 Key Laboratory of Marine Biogenetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen, Fujian, China. Electronic address: wywang@tio.org.cn.
  • 4 Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai, China.
  • 5 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang, China. Electronic address: chengxd@zjcc.org.cn.
  • 6 The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China; Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, Zhejiang, China. Electronic address: jqin@ucas.ac.cn.
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 (Kd= 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.

Keywords

C188–9 (PubChem CID: 1324494); Dual inhibition; Gastric cancer; MYC; SLC39A10; STAT3 inhibitor; XYA-2 (PubChem CID: 156012778).

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