通过抑制 DCLK1/STAT3 信号通路,重新利用 diacerein 抑制结直肠癌生长

IF 4 2区 医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Chinese Journal of Natural Medicines Pub Date : 2024-04-01 DOI:10.1016/S1875-5364(24)60621-7
Qiaobei YE , Yu ZHU , Meng SHI , Linxi LV , Yuyan GONG , Luyao ZHANG , Lehe YANG , Haiyang ZHAO , Chengguang ZHAO , Huanhai XU
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引用次数: 0

摘要

双皮质素样激酶 1 (DCLK1) 在各种癌症中都有较高的表达水平,尤其是在人类结直肠癌 (CRC) 中。Diacerein是一种临床批准的白细胞介素(IL)-1β抑制剂,用于治疗骨关节炎,研究人员通过体外和体内分析评估了它对CRC增殖和迁移的影响及其潜在机制。研究采用了 MTT 试验、集落形成、伤口愈合、透孔试验、流式细胞术和 Hoechst 33342 染色法来评估细胞增殖、迁移和凋亡。此外,还进行了蛋白质组芯片分析和 Western 印迹分析,以阐明迪卡瑞林的具体作用机制。我们的研究结果表明,迪卡西林能显著抑制体外和体内依赖 DCLK1 的 CRC 生长。通过高通量蛋白质组学芯片和分子对接研究,我们发现 diacerein 与 DCLK1 直接相互作用。从机理上讲,我们观察到 diacerein 或特异性 DCLK1 siRNA 抑制 DCLK1 后 p-STAT3 的表达。此外,diacerein 还有效地破坏了 DCLK1/STAT3 信号通路及其下游靶标,包括 MCL-1、VEGF 和 survivin,从而抑制了小鼠模型中 CRC 的进展。
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Repurposing diacerein to suppress colorectal cancer growth by inhibiting the DCLK1/STAT3 signaling pathway

Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1β inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein’s specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.

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来源期刊
Chinese Journal of Natural Medicines
Chinese Journal of Natural Medicines INTEGRATIVE & COMPLEMENTARY MEDICINE-PHARMACOLOGY & PHARMACY
CiteScore
7.50
自引率
4.30%
发文量
2235
期刊介绍: The Chinese Journal of Natural Medicines (CJNM), founded and sponsored in May 2003 by China Pharmaceutical University and the Chinese Pharmaceutical Association, is devoted to communication among pharmaceutical and medical scientists interested in the advancement of Traditional Chinese Medicines (TCM). CJNM publishes articles relating to a broad spectrum of bioactive natural products, leading compounds and medicines derived from Traditional Chinese Medicines (TCM). Topics covered by the journal are: Resources of Traditional Chinese Medicines; Interaction and complexity of prescription; Natural Products Chemistry (including structure modification, semi-and total synthesis, bio-transformation); Pharmacology of natural products and prescription (including pharmacokinetics and toxicology); Pharmaceutics and Analytical Methods of natural products.
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