Atractylenolide-I Suppresses Tumorigenesis of Breast Cancer by Inhibiting Toll-Like Receptor 4-Mediated Nuclear Factor-κB Signaling Pathway

Abstract

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.

Atractylenolide-I Sensitizes Triple-Negative Breast Cancer Cells to Paclitaxel by Blocking CTGF Expression and Fibroblast Activation

“…A human CTGF/CCN2 DuoSet ELISA kit and recombinant human CTGF protein (rCTGF) were purchased from R&D Systems (Minneapolis, MN, USA). AT-1 was used at a dose of 0-100 μM ( 17 ). rCTGF was used at a dose of 0-20 μg/mL ( 38 ).…”

“…Atractylenolide-I (ATL-1) is a naturally occurring sesquiterpene lactone isolated from Atractylodes macrocephala Koidz [Family: Compositae] ( 12 , 13 ) that has been applied in anti-inflammatory, antifibrotic and antitumor treatments ( 14 – 18 ). ATL-1 has antitumor effects on a variety of cancers, including colon cancer ( 18 , 19 ), breast cancer ( 17 ), melanoma ( 20 ), ovarian cancer ( 21 , 22 ) and gastric cancer ( 23 ). ATL-1 can inhibit the proliferation of tumor cells ( 17 , 19 ) and induce apoptosis in tumor cells ( 18 ).…”

“…ATL-1 has antitumor effects on a variety of cancers, including colon cancer ( 18 , 19 ), breast cancer ( 17 ), melanoma ( 20 ), ovarian cancer ( 21 , 22 ) and gastric cancer ( 23 ). ATL-1 can inhibit the proliferation of tumor cells ( 17 , 19 ) and induce apoptosis in tumor cells ( 18 ). In addition, ATL-1 was found to reduce the dryness of tumor cells and increase the sensitivity of tumor cells to paclitaxel ( 22 ).…”

Atractylenolide I Inhibits NLRP3 Inflammasome Activation in Colitis-Associated Colorectal Cancer via Suppressing Drp1-Mediated Mitochondrial Fission

“…In recent years, naturally occurring chemical substances have attracted attention because they are recognized as cancer-preventive agents with low toxicity and high anti-inflammatory effects. Atractylenolide I (ATR I), the main biologically active ingredient in Atractylodes macrocephala, also has a variety of therapeutic activities, including antitumor and anti-inflammatory effects (Long et al, 2020). Atractylenolide I inhibits the occurrence of breast cancer by inhibiting the nuclear factor-κB signaling pathway mediated by toll-like receptor 4 (Long et al, 2020).…”

“…Atractylenolide I (ATR I), the main biologically active ingredient in Atractylodes macrocephala, also has a variety of therapeutic activities, including antitumor and anti-inflammatory effects (Long et al, 2020). Atractylenolide I inhibits the occurrence of breast cancer by inhibiting the nuclear factor-κB signaling pathway mediated by toll-like receptor 4 (Long et al, 2020). Atractylenolide I could reduce LPS-induced lung injury in mice (Zhang et al, 2015), inhibit LPS-induced NO release, and reduce the level of proinflammatory cytokines in BV-2 cells (More and Choi, 2017).…”