去甲基zeylastal (T-96)通过lsd1介导的表观遗传机制对三阴性乳腺癌的抗肿瘤作用。

IF 2.6 4区 医学 Q3 CELL BIOLOGY
Analytical Cellular Pathology Pub Date : 2022-10-12 eCollection Date: 2022-01-01 DOI:10.1155/2022/2522597
Zhengjie Shen, Yongjuan Gu, Ruiyang Jiang, Heya Qian, Siyuan Li, Lixian Xu, Wenzhe Gu, Yun Zuo
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引用次数: 0

摘要

背景和目的。乳腺癌在女性肿瘤中发病率居首位。三阴性乳腺癌(TNBC)是乳腺癌的一种,其侵袭性更强,预后更差。我们前期研究发现,T96可通过抑制典型和非典型TGF-β信号通路抑制TNBC的侵袭。然而,T-96对TNBC的抗肿瘤作用及其机制尚未见研究。本研究旨在探讨T-96对乳腺癌的抗肿瘤作用及其机制。实验方法。采用MTT法、活细胞法、死细胞法和TUNEL法观察T-96对乳腺癌细胞的抗肿瘤作用。利用LSD1的siRNA、Co-IP、分子对接等方法探索T-96的直接靶点及作用机制。采用小鼠皮下异种移植模型检测T-96在体内的抗肿瘤活性。关键的结果。T-96更容易诱导高转移性TNBC细胞株凋亡(SUM-1315)。异常水平的组蛋白甲基化是转移性癌细胞的一个重要特征。LSD1是一种组蛋白去甲基酶。我们发现T-96可以显著降低LSD1蛋白的表达,增加其靶蛋白PTEN的表达,增强组蛋白甲基化。T-96还能下调PTEN可阻断的PI3K/AKT信号通路。siRNA敲低LSD1可阻断T-96的药理活性。分子对接预测了T-96通过氢键对LSD1的加工亲和力。最后,T-96在小鼠SUM-1315细胞异种移植模型中进行评价。T-96能明显抑制肿瘤生长,无明显毒性。结论和意义。结果表明,T-96通过灭活LSD1功能,在高转移性TNBC中发挥抗肿瘤活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Antitumor Effect of Demethylzeylasteral (T-96) on Triple-Negative Breast Cancer via LSD1-Mediate Epigenetic Mechanisms.

Antitumor Effect of Demethylzeylasteral (T-96) on Triple-Negative Breast Cancer via LSD1-Mediate Epigenetic Mechanisms.

Antitumor Effect of Demethylzeylasteral (T-96) on Triple-Negative Breast Cancer via LSD1-Mediate Epigenetic Mechanisms.

Antitumor Effect of Demethylzeylasteral (T-96) on Triple-Negative Breast Cancer via LSD1-Mediate Epigenetic Mechanisms.

Background and Purpose. Breast cancer ranks first in the incidence of female tumors. Triple-negative breast cancer (TNBC), one type of breast cancer, is more aggressive and has a worse prognosis. Demethylzeylasteral (T-96) is isolated from Tripterygium wilfordii Hook F. Our previous study found that T96 could inhibit TNBC invasion via suppressing the canonical and noncanonical TGF-β signaling pathways. However, the antitumor effects and mechanisms of T-96 on TNBC have not been studied. This study is aimed at investigating the antitumor effect and mechanism of T-96 on breast cancer. Experimental approach. MTT assay, Live and Dead cell assay, and TUNEL were used to observe the antitumor effect of breast cancer cells treated with T-96. siRNA of LSD1, Co-IP, and molecular docking were used to explore the direct target and mechanism of T-96. Subcutaneous murine xenograft models were used to detect the efficacy of T-96 antitumor activity in vivo. Key Results. T-96 was more susceptible to inducing the apoptosis of highly metastatic TNBC cell lines (SUM-1315). An abnormal level of histone methylation is a crucial characteristic of metastatic cancer cells. LSD1 is a histone demethylase. We found that T-96 could significantly decrease the protein expression of LSD1, increase its target protein PTEN expression and enhance histone methylation. T-96 could also down-regulate the PI3K/AKT signaling pathway, which could be blocked by PTEN. Knockdown of LSD1 by siRNA blocked the pharmacological activity of T-96. And the molecular docking predicted T-96 processed affinity toward LSD1 through hydrogen bonding. Finally, T-96 was evaluated in a murine xenograft model of SUM-1315 cells. And T-96 could significantly inhibit tumor growth without showing marked toxicity. Conclusions & Implications. The results illustrated that T-96 exerted antitumor activity in highly metastatic TNBC by inactivating the LSD1 function.

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来源期刊
Analytical Cellular Pathology
Analytical Cellular Pathology ONCOLOGY-CELL BIOLOGY
CiteScore
4.90
自引率
3.10%
发文量
70
审稿时长
16 weeks
期刊介绍: Analytical Cellular Pathology is a peer-reviewed, Open Access journal that provides a forum for scientists, medical practitioners and pathologists working in the area of cellular pathology. The journal publishes original research articles, review articles, and clinical studies related to cytology, carcinogenesis, cell receptors, biomarkers, diagnostic pathology, immunopathology, and hematology.
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