盐酸石蒜碱通过胆固醇生物合成和PTPN11核转位抑制胆管癌。

Lycorine hydrochloride inhibits cholangiocarcinoma through cholesterol biosynthesis and PTPN11 nuclear translocation.

作者信息

Zhao Fengyun, Peng Shuxian, Zou Liming, Zhong Mingtian, Huang Yanni, Wang Ping, Ji Mingfang, Ma Xiaodong, Li Fugui

机构信息

Zhongshan City People's Hospital, Cancer Research Institute of Zhongshan City, Guangdong Province, Zhongshan City, 528403, China.

Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Guangdong Key Laboratory of Mental Health and Cognitive Science, Center for Studies of Psychological Application, Institute for Brain Research and Rehabilitation, South China Normal University, Guangdong province, Guangzhou City, 510630, China.

出版信息

Cell Commun Signal. 2025 Jul 1;23(1):315. doi: 10.1186/s12964-025-02318-5.

DOI:10.1186/s12964-025-02318-5

PMID:40598214

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12220003/

Abstract

BACKGROUND

Intrahepatic Cholangiocarcinoma (ICC) is a highly aggressive malignancy with limited treatment options. Identifying novel therapeutic agents for ICC is crucial. Numerous natural compounds have demonstrated remarkable anti-tumor activities and can enhance the efficacy of chemotherapy. Thus, our study aimed to screen natural compounds for their anti-ICC effects.

METHODS

A total of 640 natural compounds were screened using a cell viability assay to identify potential compounds that could inhibit the proliferation of ICC cells. The anti-ICC effects of Lycorine Hydrochloride (LY) were confirmed through cell proliferation, colony formation, cell cycle, migration, and invasion assays, as well as in xenograft models. Bioinformatics analyses and validation experiments (Quantitative real-time PCR, Western blot, and immunostaining assays) were utilized to investigate the roles of genes (SQLE, FDFT1, and PTPN11) in ICC. RNA sequencing and immunofluorescence staining were performed to elucidate underlying molecular mechanisms.

RESULTS

LY was identified as a potential ICC inhibitor, exhibiting anti-ICC effects both in vitro and in vivo. Mechanistically, LY inhibited cholesterol synthesis in tumor cells by down-regulating the expression of SQLE and FDFT1. The knockdown of SQLE or FDFT1 significantly inhibited ICC cell proliferation and colony formation. RNA sequencing confirmed that inhibition of FDFT1 suppressed the cholesterol biosynthesis pathway, while SQLE inhibition affected specific oncogenic pathways. Additionally, immunofluorescence staining revealed that down-regulation of SQLE reduced PTPN11 expression and inhibited its nuclear translocation. Furthermore, pharmacological inhibition of SQLE and FDFT1 by LY significantly enhanced sensitivity to several common chemotherapeutic drugs for ICC. Notably, the combination of LY and Gemcitabine (GEM) displayed the most potent synergistic anti-tumor effect across various tumor types.

CONCLUSION

These findings identify Lycorine Hydrochloride as a promising treatment alternative for ICC and propose a novel combination strategy (LY + GEM) for treating multiple solid tumors.

摘要

背景

肝内胆管癌（ICC）是一种侵袭性很强的恶性肿瘤，治疗选择有限。确定ICC的新型治疗药物至关重要。许多天然化合物已显示出显著的抗肿瘤活性，并可增强化疗效果。因此，我们的研究旨在筛选具有抗ICC作用的天然化合物。

方法

使用细胞活力测定法筛选了总共640种天然化合物，以鉴定可能抑制ICC细胞增殖的潜在化合物。通过细胞增殖、集落形成、细胞周期、迁移和侵袭测定以及异种移植模型，证实了盐酸石蒜碱（LY）的抗ICC作用。利用生物信息学分析和验证实验（定量实时PCR、蛋白质印迹和免疫染色测定）来研究基因（SQLE、FDFT1和PTPN11）在ICC中的作用。进行RNA测序和免疫荧光染色以阐明潜在的分子机制。

结果

LY被鉴定为一种潜在的ICC抑制剂，在体外和体内均表现出抗ICC作用。从机制上讲，LY通过下调SQLE和FDFT1的表达来抑制肿瘤细胞中的胆固醇合成。敲低SQLE或FDFT1可显著抑制ICC细胞增殖和集落形成。RNA测序证实，抑制FDFT1可抑制胆固醇生物合成途径，而抑制SQLE则影响特定的致癌途径。此外，免疫荧光染色显示，SQLE的下调降低了PTPN11的表达并抑制了其核转位。此外，LY对SQLE和FDFT1的药理抑制作用显著增强了ICC对几种常用化疗药物的敏感性。值得注意的是，LY与吉西他滨（GEM）的联合在各种肿瘤类型中显示出最有效的协同抗肿瘤作用。