Abstract
Invasive breast cancer is highly regulated by tumor-derived cytokines in tumor microenvironment. The development of drugs that specifically target cytokines are promising in breast cancer treatment. In this study, we reported that arctigenin, a bioactive compound from Arctium lappa L., could decrease tumor-promoting cytokines GM-CSF, MMP-3, MMP-9 and TSLP in breast cancer cells. Arctigenin not only inhibited the proliferation, but also the invasion and stemness of breast cancer cells via decreasing GM-CSF and TSLP. Mechanistically, arctigenin decreased the promoter activities of GM-CSF and TSLP via reducing the nuclear translocation of NF-κB p65 which is crucial for the transcription of GM-CSF and TSLP. Furthermore, arctigenin-induced depletion of GM-CSF and TSLP inhibited STAT3 phosphorylation and β-catenin signaling resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo. Our findings provide new insights into the mechanism by which tumor-promoting cytokines regulate breast cancer progression and suggest that arctigenin is a promising candidate for cytokine-targeted breast cancer therapy.
Highlights
Breast cancer is considered the most common cancer for women worldwide and it is the second leading cause of cancer-related deaths among females in the world [1,2]
Immunohistochemistry demonstrated that arctigenin treatment markedly reduced the expression of Ki-67 in tumor tissues which is associated with cellular proliferation (Figure 1F)
Arctigenin was able to decrease TNF-α-stimulated nuclear expression and localization of p65 in 4T1 cells (Figure 3G,H), suggesting that arctigenin inhibits p65 nuclear translocation. These results indicate that arctigenin decreases the promoter activities of granulocyte macrophage colony-stimulating factor (GM-CSF) and thymic stromal lymphopoietin (TSLP) through inhibiting NF-κB activation
Summary
Breast cancer is considered the most common cancer for women worldwide and it is the second leading cause of cancer-related deaths among females in the world [1,2]. Numerous tumor-derived cytokines including granulocyte macrophage colony-stimulating factor (GM-CSF), thymic stromal lymphopoietin (TSLP), matrix metalloproteinase 3 (MMP-3) and matrix metalloproteinase 9 (MMP-9) have been reported to contribute to breast cancer progression [9,10,11]. STAT3 pathway and β-catenin signaling are frequently dysregulated in breast cancer, contributing to cancer stem cells (CSCs)-associated tumor initiation, angiogenesis, metastasis, therapy resistance, and tumor relapse [13,14]. The effect of arctigenin on tumor-derived cytokines in the microenvironment of breast cancer was investigated. Arctigenin decreased the promoter activities of GM-CSF and TSLP via hindering the nuclear translocation of NF-κB p65, and inhibited STAT3/β-catenin signaling, resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo
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