Marine derived macrolide bryostatin 4 inhibits the TGF-β signaling pathway against acute erythroleukemia.

IF 4.9 2区 医学 Q2 CELL BIOLOGY Cellular Oncology Pub Date : 2024-10-01 Epub Date: 2024-07-31 DOI:10.1007/s13402-024-00968-0
Yan-Yu Kou, Jie Liu, Yung-Ting Chang, Li-Yun Liu, Fan Sun, Yi-Lin Li, Jia-Rong Leng, Hou-Wen Lin, Fan Yang
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Abstract

Purpose: Acute erythroleukemia (AEL) is a rare and highly aggressive subtype of acute myeloid leukemia (AML) with an extremely poor prognosis when treated with available drugs. Therefore, new investigational agents capable of inducing remission are urgently required.

Methods: Bioinformatics analysis, western blot and qRT-PCR were used to reveal the potential biological mechanism of bryostatin 4 (B4), an antineoplastic macrolide derived from the marine bryozoan Bugula neritina. Then, in vivo experiments were conducted to evaluate the role of transforming growth factor (TGF)-β signaling in the progression of AEL.

Results: Our results revealed that the proliferation of K562 cells and TF-1 cells was significantly inhibited by B4 at IC50 values of 37 nM and 52 nM, respectively. B4 inhibited TGF-β signaling and its downstream pathway targets, particularly the phosphorylation of Smad2, Smad3, Ras, C-RAF, ERK1/2, and MEK. B4 also played an important role in cell invasion and migration in K562 cells and TF-1 cells by reducing the protein levels of the mesenchymal cell marker vimentin. Moreover, Flow cytometry and western blot analyses demonstrated that B4 induced apoptosis and initiated G0/G1 phase arrest by modulating mitochondrial dysfunction and cyclin-dependent kinase (CDK) expression.

Conclusion: These findings indicated that B4 could inhibit the proliferation, migration, invasion, and TGF-β signaling pathways of AEL cells, thus suggesting that B4 possesses therapeutic potential as a treatment for AEL.

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海洋衍生大环内酯类药物白屈菜素 4 可抑制 TGF-β 信号通路,对抗急性红细胞白血病。
目的:急性红细胞白血病(AEL)是急性髓性白血病(AML)的一种罕见且侵袭性极强的亚型,用现有药物治疗预后极差。因此,迫切需要能够诱导病情缓解的新研究药物:方法:采用生物信息学分析、Western 印迹和 qRT-PCR 技术揭示了从海洋贝类 Bugula neritina 中提取的抗肿瘤大环内酯类药物--白僵菌素 4(B4)的潜在生物机制。然后,进行了体内实验以评估转化生长因子(TGF)-β信号在AEL进展过程中的作用:结果表明,B4能显著抑制K562细胞和TF-1细胞的增殖,IC50值分别为37 nM和52 nM。B4 可抑制 TGF-β 信号转导及其下游通路靶点,尤其是 Smad2、Smad3、Ras、C-RAF、ERK1/2 和 MEK 的磷酸化。B4 还通过降低间质细胞标志物波形蛋白的蛋白水平,在 K562 细胞和 TF-1 细胞的侵袭和迁移中发挥了重要作用。此外,流式细胞术和 Western 印迹分析表明,B4 通过调节线粒体功能障碍和细胞周期蛋白依赖性激酶(CDK)的表达,诱导细胞凋亡并启动 G0/G1 期停滞:这些研究结果表明,B4可抑制AEL细胞的增殖、迁移、侵袭和TGF-β信号通路,从而表明B4具有治疗AEL的潜力。
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来源期刊
Cellular Oncology
Cellular Oncology ONCOLOGY-CELL BIOLOGY
CiteScore
10.30
自引率
1.50%
发文量
86
审稿时长
12 months
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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