Atractylenolide-I Suppresses Tumorigenesis of Breast Cancer by Inhibiting Toll-Like Receptor 4-Mediated Nuclear Factor-κB Signaling Pathway.
Atractylenolide-I Suppresses Tumorigenesis of Breast Cancer by Inhibiting Toll-Like Receptor 4-Mediated Nuclear Factor-κB Signaling Pathway.
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白术内酯-I 通过抑制 Toll 样受体 4 介导的核因子-κB 信号通路抑制乳腺癌肿瘤发生
DOI：
10.3389/fphar.2020.598939
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发表时间：
2020
影响因子：
5.6
通讯作者：
Wang T
中科院分区：
文献类型：
--
作者：
Long F;Lin H;Zhang X;Zhang J;Xiao H;Wang T
背景：toll样受体4 （Toll-like receptor 4, TLR4）是与肿瘤发生相关的重要传感器，TLR4在人类肿瘤中过表达往往与预后不良相关。苍术内酯ⅰ（Atractylenolide‐I, AT-I）是一种新型tlr4拮抗剂，是苍术的主要生物活性成分。越来越多的证据表明，AT-I对结直肠癌、膀胱癌和黑色素瘤等多种癌症具有抗肿瘤作用。然而，AT-I对乳腺肿瘤发生的影响尚不清楚。方法：为明确TLR4/NF-κB通路与乳腺癌的相关性，采用人组织芯片技术和免疫组织化学技术检测正常乳腺组织和不同tnm分期癌组织中TLR4和NF-κB的表达。通过MCF-7和MDA-MB-231两种乳腺癌细胞的细胞活力、集落形成、凋亡、迁移和侵袭实验，研究AT-I对肿瘤发生的影响，并建立n -亚硝基- n -甲基脲诱导的大鼠乳腺癌模型，评价AT-I在体内的抗肿瘤作用。通过一系列LPS处理和TLR4敲除实验，通过western blot和ELISA检测进一步探索可能的潜在机制。结果：我们发现TLR4和NF-κB在乳腺癌组织中显著上调，并与tnm分期晚期相关。AT-I可以抑制TLR4介导的NF-κB信号通路，降低乳腺癌细胞中NF-κB调节的细胞因子，从而抑制乳腺癌细胞的增殖、迁移和侵袭，诱导乳腺癌细胞凋亡。此外，AT-I可通过TLR4/NF-κB途径抑制n -亚硝基- n -甲基脲诱导的大鼠乳腺肿瘤进展。结论：我们的研究结果表明TLR4和NF-κB在乳腺癌中过表达，AT-I可以通过抑制TLR4介导的NF-κB信号通路抑制乳腺癌的发生。
Background: Toll-like receptor 4 (TLR4) is an essential sensor related to tumorigenesis, and overexpression of TLR4 in human tumors often correlates with poor prognosis. Atractylenolide‐I (AT-I), a novel TLR4-antagonizing agent, is a major bioactive component from Rhizoma Atractylodes Macrocephalae. Emerging evidence suggests that AT-I exerts anti-tumor effects on various cancers such as colorectal cancer, bladder cancer and melanoma. Nevertheless, the effects of AT-I on mammary tumorigenesis remain unclear. Methods: In order to ascertain the correlation of TLR4/NF-κB pathway with breast cancer, the expression of TLR4 and NF-κB in normal breast tissues and cancer tissues with different TNM-stages was detected by human tissue microarray and immunohistochemistry technology. The effects of AT-I on tumorigenesis were investigated by cell viability, colony formation, apoptosis, migration and invasion assays in two breast cancer cells (MCF-7 and MDA-MB-231), and N-Nitroso-N-methylurea induced rat breast cancer models were developed to evaluate the anti-tumor effects of AT-I in vivo. The possible underlying mechanisms were further explored by western blot and ELISA assays after a series of LPS treatment and TLR4 knockdown experiments. Results: We found that TLR4 and NF-κB were significantly up-regulated in breast cancer tissues, and was correlated with advanced TNM-stages. AT-I could inhibit TLR4 mediated NF-κB signaling pathway and decrease NF-κB-regulated cytokines in breast cancer cells, thus inhibiting cell proliferation, migration and invasion, and inducing apoptosis of breast cancer cells. Furthermore, AT-I could inhibit N-Nitroso-N-methylurea-induced rat mammary tumor progression through TLR4/NF-κB pathway. Conclusion: Our findings demonstrated that TLR4 and NF-κB were over expressed in breast cancer, and AT-I could suppress tumorigenesis of breast cancer via inhibiting TLR4-mediated NF-κB signaling pathway.
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影响因子：
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DOI：
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