Long Fangyi, Lin Hong, Zhang Xiqian, Zhang Jianhui, Xiao Hongtao, Wang Ting
Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu Medical College, Chengdu, China.
Department of Pharmacy, Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Front Pharmacol. 2020 Dec 8;11:598939. doi: 10.3389/fphar.2020.598939. eCollection 2020.
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 . 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. 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 . The possible underlying mechanisms were further explored by western blot and ELISA assays after a series of LPS treatment and TLR4 knockdown experiments. 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. 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.
Toll样受体4（TLR4）是一种与肿瘤发生相关的重要传感器，TLR4在人类肿瘤中的过表达通常与不良预后相关。白术内酯-I（AT-I）是一种新型的TLR4拮抗剂，是[来源未提及]的主要生物活性成分。新出现的证据表明，AT-I对多种癌症如结直肠癌、膀胱癌和黑色素瘤具有抗肿瘤作用。然而，AT-I对乳腺肿瘤发生的影响仍不清楚。为了确定TLR4/NF-κB通路与乳腺癌的相关性，采用人体组织芯片和免疫组化技术检测了不同TNM分期的正常乳腺组织和癌组织中TLR4和NF-κB的表达。通过细胞活力、集落形成、凋亡、迁移和侵袭实验，研究了AT-I对两种乳腺癌细胞（MCF-7和MDA-MB-231）肿瘤发生的影响，并建立了N-亚硝基-N-甲基脲诱导的大鼠乳腺癌模型来评估AT-I的抗肿瘤作用。在进行了一系列脂多糖处理和TLR4敲低实验后，通过蛋白质免疫印迹和酶联免疫吸附测定进一步探索了可能的潜在机制。我们发现，TLR4和NF-κB在乳腺癌组织中显著上调，且与晚期TNM分期相关。AT-I可抑制TLR4介导的NF-κB信号通路，降低乳腺癌细胞中NF-κB调节的细胞因子水平，从而抑制细胞增殖、迁移和侵袭，并诱导乳腺癌细胞凋亡。此外，AT-I可通过TLR4/NF-κB通路抑制N-亚硝基-N-甲基脲诱导的大鼠乳腺肿瘤进展。我们的研究结果表明，TLR4和NF-κB在乳腺癌中过表达，AT-I可通过抑制TLR4介导的NF-κB信号通路抑制乳腺癌的肿瘤发生。
