Imperatorin Suppresses Aberrant Hedgehog Pathway and Overcomes Smoothened Antagonist Resistance via STAT3 Inhibition.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-11-20 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S482894

Juan Wang, Hua Cheng, Xinyue Zhao, Xiuwen Zhang, Xiaolei Ding, Taomin Huang

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Abstract

Background: Hyperactive Hedgehog (Hh) signaling initiates and drives the progression of various tumors. Despite the clinical success of Hh inhibitors targeting Smoothened (SMO), drug resistance, often stemming from SMO mutations, remains a formidable obstacle in cancer therapy. Here, we investigated the potential of imperatorin (IMP), a Chinese herbal medicine, to overcome drug resistance and revealed the potential mechanisms.

Methods: The effect of IMP on Hh signaling pathway was evaluated via Quantitative reverse transcription-polymerase chain reaction, Dual-luciferase reporter assay and Western blot. Meanwhile, we tested its ani-proliferative potential on Hh-driven tumor cells. Loss/gain-of-function, network pharmacology analysis, RNA-sequence analysis and molecular docking were performed to investigate the potential mechanisms of IMP-mediated functions. Furthermore, we established a subcutaneous Hh-driven medulloblastoma xenograft model using the DAOY cell line and examined the in vivo therapeutic efficacy of IMP.

Results: We identified IMP as a novel Hh inhibitor capable of overcoming drug-resistance caused by SMO mutants by inhibiting downstream transcription factor GLI1. IMP suppressed the proliferation of Hh-dependent cancer cells along with Hh activity inhibition. Mechanistically, IMP attenuated the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and its interaction with GLI1 promoter, consequently blocking GLI1 transcription and the target gene expressions. Molecular docking analysis revealed the favorable binding affinity between IMP and STAT3. Importantly, IMP application effectively inhibited the growth of medulloblastoma in vivo, accompanied by the downregulation of GLI1 and phosphorylated STAT3.

Conclusion: Our findings revealed IMP as an innovative approach to combat the drug resistance of SMO inhibitors in Hh-driven tumors, highlighting the crucial role of STAT3 as a transcriptional regulator in Hh signaling.

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Imperatorin 通过抑制 STAT3 抑制异常的刺猬蛋白通路并克服 Smoothened 拮抗剂的抗性

背景：过度活跃的刺猬（Hh）信号引发并推动各种肿瘤的进展。尽管靶向 Smoothened（SMO）的 Hh 抑制剂在临床上取得了成功，但往往源于 SMO 突变的耐药性仍然是癌症治疗中的一个巨大障碍。在此，我们研究了一种中草药--白花蛇舌草素（IMP）克服耐药性的潜力，并揭示了其潜在机制：方法：通过定量反转录聚合酶链式反应、双荧光素酶报告实验和Western印迹检测IMP对Hh信号通路的影响。同时，我们还测试了 IMP 对 Hh 驱动的肿瘤细胞的增殖潜力。通过功能缺失/功能增强、网络药理学分析、RNA序列分析和分子对接研究了IMP介导功能的潜在机制。此外，我们利用 DAOY 细胞系建立了 Hh 驱动的髓母细胞瘤皮下异种移植模型，并研究了 IMP 的体内疗效：结果：我们发现IMP是一种新型Hh抑制剂，能够通过抑制下游转录因子GLI1克服SMO突变体产生的耐药性。在抑制 Hh 活性的同时，IMP 还能抑制 Hh 依赖性癌细胞的增殖。从机理上讲，IMP 可抑制信号转导和转录激活因子 3（STAT3）的磷酸化及其与 GLI1 启动子的相互作用，从而阻断 GLI1 的转录和靶基因的表达。分子对接分析表明，IMP 与 STAT3 具有良好的结合亲和力。重要的是，在体内应用 IMP 能有效抑制髓母细胞瘤的生长，同时下调 GLI1 和磷酸化 STAT3：我们的研究结果表明，IMP是对抗Hh驱动肿瘤中SMO抑制剂耐药性的一种创新方法，突出了STAT3作为Hh信号转导中转录调节因子的关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.