蓬尼定通过降低 FOXO4 表达来抑制胆囊癌增殖和转移，下调 MAGEB2 表达。
Ponicidin inhibited gallbladder cancer proliferation and metastasis by decreasing MAGEB2 expression through FOXO4.
机构信息
Laboratory of General Surgery and Department of General Surgery, Xinhua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China; Shanghai Key Laboratory of Biliary Tract Disease Research, No. 1665 Kongjiang Road, Shanghai 200092, China.
Department of endoscopic diagnosis and treatment of digestive diseases, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China.
出版信息
Phytomedicine. 2023 Jun;114:154785. doi: 10.1016/j.phymed.2023.154785. Epub 2023 Mar 26.
BACKGROUND
Gallbladder cancer (GBC) is the most aggressively malignant tumor in the bile duct system. The prognosis for patients with GBC is extremely poor. Ponicidin is a diterpenoid compound extracted and purified from the traditional Chinese herb Rabdosia rubescens, and showed promising anti-cancer effects in a variety of tumors. However, Ponicidin has not been investigated in GBC.
METHODS
CCK-8, colony formation assay and EdU-488 DNA synthesis assay were performed to investigate the effect of Ponicidin on GBC cells proliferation. Cell invasion and migration assays and wound-healing assay were used to explore the effect of Ponicidin on invasion and migration ability of GBC cells. mRNA-seq was adopted to explore the underlying mechanisms. Western blot and immunohistochemical staining were conducted to detect the protein level. CHIP assay and dual-luciferase assay were used to validate binding motif. Nude mouse model of GBC was used to assess the anti-tumor effect and safety of Ponicidin.
RESULTS
Ponicidin inhibited the proliferation and cell invasion and migration of GBC cells in vitro. Moreover, Ponicidin exerted anti-tumor effects by down-regulating the expression of MAGEB2. Mechanically, Ponicidin upregulated the FOXO4 expression and promoted it to accumulate in nucleus to inhibit the transcript of MAGEB2. Furthermore, Ponicidin suppressed tumor growth in the nude mouse model of GBC with excellent safety.
CONCLUSION
Ponicidin may be a promising agent for the treatment of GBC effectively and safely.
背景
胆囊癌（GBC）是胆管系统中最具侵袭性的恶性肿瘤。GBC 患者的预后极差。蓬尼定是从中国传统草药冬凌草中提取和纯化的二萜类化合物，在多种肿瘤中显示出有希望的抗癌作用。然而，蓬尼定尚未在 GBC 中进行研究。
方法
CCK-8、集落形成实验和 EdU-488 DNA 合成实验用于研究蓬尼定对 GBC 细胞增殖的影响。细胞侵袭和迁移实验以及划痕愈合实验用于探索蓬尼定对 GBC 细胞侵袭和迁移能力的影响。采用 mRNA-seq 技术探索潜在机制。Western blot 和免疫组化染色检测蛋白水平。CHIP 实验和双荧光素酶实验用于验证结合基序。建立 GBC 裸鼠模型评估蓬尼定的抗肿瘤作用和安全性。
结果
蓬尼定抑制 GBC 细胞在体外的增殖、细胞侵袭和迁移。此外，蓬尼定通过下调 MAGEB2 的表达发挥抗肿瘤作用。机制上，蓬尼定上调 FOXO4 的表达并促进其在核内积累，从而抑制 MAGEB2 的转录。此外，蓬尼定在 GBC 裸鼠模型中具有良好的安全性，抑制了肿瘤生长。
结论
蓬尼定可能是一种有效且安全的治疗 GBC 的有前途的药物。
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