Aloperine在胆囊癌中发挥抗肿瘤作用，激活肿瘤细胞内禀STING通路

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-09-23 DOI:10.1016/j.intimp.2025.115590

Yushun Chang , Jie Lin , Bo Yang , Yuxuan Shen , Weijun Zhao , Hao Shen , Quan Yang , Haowen Lu , Xiujun Cai , Yifan Wang , Wen Hua

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引用次数: 0

摘要

operine （ALO）是一种从天然中草药中分离出来的喹诺齐啶类生物碱，在多种恶性肿瘤中具有抗肿瘤活性，但其在胆囊癌（GBC）中的疗效和机制尚不清楚。方法采用ALO处理人GBC细胞株，观察细胞活力、菌落形成、5-乙基-2′-脱氧尿苷（EdU）结合及凋亡情况。免疫印迹法和免疫荧光法检测自噬通量和相关信号。在裸鼠异种移植瘤模型中测定了体内抗肿瘤活性。结果salo明显抑制了GBCs的增殖能力，破坏了自噬体与溶酶体的融合，导致活性氧（ROS）积累和细胞凋亡。此外，ALO诱导DNA损伤和双链DNA （dsDNA）向细胞质的核释放，导致环gmp - amp合成酶(cGAS) -干扰素基因刺激因子（STING）介导的干扰素（IFN）通路激活，增强体外自然杀伤细胞（NK细胞）的激活。在体内，ALO减少了皮下GBCs异种移植物的体积和重量，并增加了肿瘤组织中cleaved caspase-3和BAX的表达，证实了肿瘤细胞的凋亡。结论ALO可能通过抑制自噬通量诱导ros介导的细胞凋亡，同时激活cGAS-STING-IFN通路，增强抗肿瘤免疫，从而成为胆囊癌治疗的新候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Aloperine exerts anti-tumor effect and activates the tumor cell-intrinsic STING pathway in gallbladder cancer

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Aloperine exerts anti-tumor effect and activates the tumor cell-intrinsic STING pathway in gallbladder cancer

Background

Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, exhibits anticancer activity in several malignancies, but its efficacy and mechanisms in gallbladder cancer (GBC) remain undefined.

Methods

Human GBC cell lines (GBCs) were treated with ALO and assessed for viability, colony formation, 5-Ethynyl-2′-deoxyuridine (EdU) incorporation and apoptosis. Autophagic flux and related signaling were evaluated by western blotting and immunofluorescence. In vivo antitumor activity was determined in a nude mouse xenograft model.

Results

ALO markedly inhibited the proliferation ability of GBCs and disrupted autophagosome–lysosome fusion, leading to reactive oxygen species (ROS) accumulation and apoptosis. Furthermore, ALO induced DNA damage and nuclear release of double-stranded DNA (dsDNA) to cytoplasm, leading to cyclic-GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-mediated interferon (IFN) pathway activation and enhancing natural killer cells (NK cells) activation in vitro. In vivo, ALO reduced subcutaneous GBCs xenograft volume and weight and, along with increased cleaved caspase-3 and BAX expression in tumor tissues, confirming tumor cell apoptosis.

Conclusions

These findings indicate that ALO may serve as a novel therapeutic candidate for gallbladder cancer by inhibiting autophagic flux to induce ROS-mediated apoptosis while activating the cGAS–STING–IFN pathway to enhance antitumor immunity.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.