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Int J Biol Sci 2023; 19(4):1063-1079. doi:10.7150/ijbs.80324 This issue Cite

Research Paper

Polyphyllin B Suppresses Gastric Tumor Growth by Modulating Iron Metabolism and Inducing Ferroptosis

Can Hu^1,5,6#, Dan Zu^1#, Jingli Xu^1,5,6#, Hangdong Xu^1#, Li Yuan^2,5,6, Jiahui Chen^1,5,6, Qin Wei^3,5,6, Yanqiang Zhang^1,5,6, Jing Han⁴, Tao Lu¹, Jinyun Dong^1,5,6✉, Jiang-Jiang Qin^1,5,6✉, Zhiyuan Xu^1,5,6✉, Xiangdong Cheng^1,5,6✉

1. Department of Gastric surgery, Zhejiang Cancer Hospital, Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
2. Department of Integrated Chinese and Western medicine, Zhejiang Cancer Hospital, Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
3. Department of Abdominal Oncology, Zhejiang Cancer Hospital, Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China.
4. Biospecimen Repository, Cancer Hospital of the University of Chinese Academy of Sciences.
5. Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China.
6. Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Xiangdong Cheng, Department of Gastric surgery, Zhejiang Cancer Hospital, Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China. E-mail: chengxdorg.cn; Zhiyuan Xu, Department of Gastric surgery, Zhejiang Cancer Hospital, Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China. E-mail: xuzyrog.cn; Jiang-Jiang Qin, Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China. E-mail: zylysjtucom. Jinyun Dong, Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou 310022, China. E-mail: dongjinyun1989com. More

Abstract

Gastric cancer (GC) is one of the most common malignant tumors in the world. GPx4, as the core regulator of ferroptosis, has become a potential molecular target for developing anticancer agents. In the present study, we found that GPx4 was overexpressed and negatively correlated with poor prognosis in GC, while it was associated with the GC development. Molecular docking and structure-based virtual screening assays were used to screen potential GPx4 inhibitors, and we identified a novel GPx4 inhibitor, polyphyllin B (PB), which can induce ferroptosis by down-regulating GPx4 expression in GC cells. It has also been shown to inhibit cell proliferation, suppress invasion and migration, induce apoptosis, and block the cell cycle progression in GC cells in vitro. Then, immunofluorescence and western blotting assay confirmed that PB can regulate the expression of LC3B, TFR1, NOCA4 and FTH1 in vitro, which suggested that suggest that PB may increase the level of Fe²⁺ by transporting Fe³⁺ into the cell by TFR1 and promoting NCOA4-dependent iron autophagy. In addition, PB can also suppresses tumor growth in an orthotopic mouse model of GC via regulating the expression of GPx4, TFR1, NOCA4 and FTH1 in vivo. In summary, we confirmed that GPx4 may be a potential target for GC treatment, PB may be a novel and promising drug for the treatment of GC, which shows good antitumor efficacy without causing significant host toxicity via inducing ferroptosis in both gastric cancer cells and mouse models.

Keywords: Gastric cancer, GPx4, ferroptosis, iron ion metabolism, natural product

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