Tigecycline suppresses colon cancer stem cells and impairs tumor engraftment by targeting SNAI1-regulated epithelial-mesenchymal transition.

IF 8.4 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Antonio Jesús Ruiz-Malagón, María Jesús Rodríguez-Sojo, Jorge García-García, Ailec Ho-Plagaro, Federico García, Teresa Vezza, Eduardo Redondo-Cerezo, Carmen Griñán-Lisón, Juan Antonio Marchal, María Elena Rodríguez-Cabezas, Alba Rodríguez-Nogales, Julio Gálvez
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引用次数: 0

Abstract

Cancer stem cells (CSCs) play a key role in the progression of colorectal cancer (CRC). The high heterogeneity of CSCs has hindered the clinical application of CSC-targeting therapies. Tetracyclines are drugs with therapeutic potentials beyond their antibiotic activity. We previously demonstrated the efficacy of tigecycline, a third-generation tetracycline, against a model of colitis-associated colorectal cancer, primarily focusing on its immunomodulatory role with a preliminary assessment of its impact on stemness. In this study we characterize the effects of tigecycline on colon CSCs in vitro and in a CRC xenograft model, with special attention on the signaling pathways involved and the modulation of the gut microbiota. We generated secondary colonospheres from two colon tumor cell lines HCT116 and CMT93, and evaluated the effect of tigecycline on CSCs properties. We showed that tigecycline (25, 50 μM) effectively reduced colon CD133+CD44+LGR5+ALDH+ subpopulations and their viability, self-renewal and migratory capacity. Moreover, tigecycline treatment hindered epithelial-mesenchymal transition (EMT) process through targeting SNAI1 and β-catenin, resulting in an upregulation of epithelial markers (E-cadherin) and a downregulation of pluripotency and mesenchymal ones (Vimentin, N-cadherin, SOX2, NANOG, MIR155, MIR146). This effect was confirmed in two independent CRC-xenograft murine models in which tigecycline administration led to a reduction in tumor volume. Finally, CRC samples were taken from HCT116 xenograft model mice for analysis of CSCs-related signaling pathways and stools were collected for gut microbiome metagenomic analysis. We found that the antibiotic modulated gut dysbiosis by increasing the abundance of beneficial bacterial species such as Parabacteroides sp., which were involved in metabolic pathways that hindered SNAI1-Wnt-β-catenin signaling. These results reinforce the new role of tigecycline in the therapy of CRC and demonstrate for the first time the effect of tigecycline on colon CSCs and their malignancies.

替加环素通过靶向snai1调控的上皮-间质转化抑制结肠癌干细胞并损害肿瘤植入。
肿瘤干细胞(CSCs)在结直肠癌(CRC)的进展中起着关键作用。csc的高异质性阻碍了csc靶向治疗的临床应用。四环素类药物的治疗潜力超出其抗生素活性。我们之前证明了替加环素(第三代四环素)对结肠炎相关结直肠癌模型的疗效,主要关注其免疫调节作用,并初步评估了其对干细胞的影响。在这项研究中,我们在体外和CRC异种移植模型中描述了替加环素对结肠CSCs的影响,特别关注了所涉及的信号通路和肠道微生物群的调节。我们从两种结肠肿瘤细胞系HCT116和CMT93中制备了次级结肠球,并评估了替加环素对CSCs性质的影响。我们发现替加环素(25,50 μM)有效降低结肠CD133+CD44+LGR5+ALDH+亚群及其活力、自我更新和迁移能力。此外,替加环素通过靶向SNAI1和β-catenin抑制上皮-间质转化(EMT)过程,导致上皮标记物(E-cadherin)上调,多能性和间质标记物(Vimentin、N-cadherin、SOX2、NANOG、MIR155、MIR146)下调。这种效果在两个独立的crc -异种移植小鼠模型中得到证实,替加环素导致肿瘤体积减少。最后,从HCT116异种移植模型小鼠中采集CRC样本,分析csc相关信号通路,并收集粪便进行肠道微生物组宏基因组分析。我们发现抗生素通过增加有益细菌种类(如Parabacteroides sp.)的丰度来调节肠道生态失调,这些有益细菌参与了阻碍SNAI1-Wnt-β-catenin信号传导的代谢途径。这些结果强化了替加环素在结直肠癌治疗中的新作用,并首次证明了替加环素对结肠CSCs及其恶性肿瘤的作用。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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