2. Academic Validation
  3. Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells

Gambogic acid induces GSDME dependent pyroptotic signaling pathway via ROS/P53/Mitochondria/Caspase-3 in ovarian cancer cells

  • Biochem Pharmacol. 2025 Feb:232:116695. doi: 10.1016/j.bcp.2024.116695.
Danya Zhang 1,  Yuxin Chen 1,  Yue Sun 1,  Hanjie Xu 2,  Rui Wei 1,  Ying Zhou 1,  Fei Li 1,  Jie Li 1,  Jing Wang 1,  Pingbo Chen 3,  Ling Xi 4
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
  • 2 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Obstetrics and Gynecology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
  • 3 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: supercpb520@163.com.
  • 4 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: lxi@tjh.tjmu.edu.cn.
PMID: 39643123 DOI: 10.1016/j.bcp.2024.116695
Abstract

Gambogic acid (GA) is a naturally active compound extracted from the Garcinia hanburyi with various Anticancer activities. However, whether GA induces Pyroptosis (a newly discovered inflammation-mediated programmed cell death mechanism) in ovarian Cancer (OC) has not yet been reported. This study revealed that GA treatment reduced cell viability by inducing Pyroptosis in OC cell lines. Typical Pyroptosis morphological manifestations such as cell swelling with large bubbles and loss of cell membrane integrity, were observed. Cleaved Caspase-3 and GSDME-N levels increased after GA treatment, and knocking out GSDME or using a Caspase-3 inhibitor could switch GA-induced cell death from Pyroptosis to Apoptosis, indicating GA induced Caspase-3/GSDME-dependent Pyroptosis. Furthermore, this research indicated that GA significantly increased Reactive Oxygen Species (ROS) and p53 phosphorylation. OC cells pretreated with ROS inhibitor N-Acetylcysteine (NAC) and the specific p53 inhibitor pifithrin-μ could completely reverse the Pyroptosis post-treatment. Elevated p53 and phosphorylated p53 reduced mitochondrial membrane potential (MMP) and Bcl-2, increase the expression of Bax, and damage mitochondria by releasing cytochrome c to activate the downstream Pyroptosis pathway. Different doses of GA inhibited tumor growth in ID8 tumor-bearing mice, and high-dose GA increased in tumor-infiltrating lymphocytes CD3, CD4, and CD8 were detected in tumor tissues. Notably, the expressions of GSDME-N, cleaved Caspase-3 and Other proteins were increased in tumor tissues with high-dose GA groups. These findings demonstrate that GA-treated OC cells could induce GSDME-mediated Pyroptosis through the ROS/p53/mitochondria signaling pathway and Caspase-3/-9 activation. Thus, GA is a promising therapeutic agent for OC treatment.

Keywords

Caspase-3/GSDME; Gambogic acid; Ovarian cancer; P53; Pyroptosis; ROS.

Figures
Products
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    Product Name
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    Target
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  • HY-12466
    ≥98.0%, Caspase-3抑制剂
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