Inhibitory Effect of Alisma canaliculatum Ethanolic Extract on NF-κB-Dependent CXCR3 and CXCL10 Expression in TNFα-Exposed MDA-MB-231 Breast Cancer Cells.

Jihye Choi,Young Lee,Sung Ahn,Soon Shin,Yoongho Lim

doi:10.3390/ijms19092607

Abstract

CXC motif chemokine ligand 10 (CXCL10) and its receptor CXC motif chemokine receptor 3 (CXCR3), play important roles in the motility of breast cancer cells. Alisma canaliculatum is a herb that has been used as a traditional medicine for thousands of years in Korea and China. Whether A. canaliculatum inhibits the motility of metastatic breast cancer cells is not clear yet. In this study, we show that A. canaliculatum ethanolic extract (ACE) prevented tumor necrosis factor-alpha (TNFα)-induced migration of MDA-MB-231 cells. ACE significantly attenuated TNFα-induced upregulation of CXCL10 and CXCR3 expression at the gene promoter level. Mechanistically, ACE inhibits TNFα-induced phosphorylation of inhibitor of κB (IκB) kinase (IKK), IκB and p65/RelA, leading to the suppression of nuclear translocation of p65/RelA nuclear factor kappa-B (NF-κB). Also, ACE inhibited NF-κB-dependent CXCR3 and CXCL10 promoter activities. These results suggest that ACE abrogates TNFα-induced migration of MDA-MB-231 breast cancer cells through down-regulation of IKK-NF-κB-dependent CXCR3 and CXCL10 expression. Our results suggest that ACE has potential as a herbal supplement for the inhibition of breast cancer metastasis.

Highlights

Breast cancer is the most common type of cancer in women worldwide
Our results show that A. canaliculatum ethanolic extract (ACE) prevents TNFα-induced migration of MDA-MB-231 metastatic breast cancer cells and inhibits TNFα-induced CXC motif chemokine receptor 3 (CXCR3) and CXC motif chemokine ligand 10 (CXCL10) expression through inhibition of the inhibitor of κB (IκB) kinase (IKK)-mediated NF-κB pathway
ACE did not show significant cytotoxic activity when used at a concentration of 20 μg/mL for 24 h (p > 0.05 with Sidak multiple comparisons test applied), cell viability was slightly reduced when treated with the same concentration for 48 h (Figure 1)

Summary

Introduction

Breast cancer is the most common type of cancer in women worldwide. Metastasis is the uncontrolled spreading of primary tumor cells to distant organs or tissues in the body. It is well established that CC motif chemokine ligand 5 (CCL5), called RANTES, from mesenchymal stem cells and CCL18 from tumor-associated macrophages act on breast cancer cells to enhance cancer motility, invasion and metastasis [13,14]. Binding of CXCL10 to its receptor CXC motif chemokine receptor 3 (CXCR3) stimulates chemotaxis of monocytes [15], dendritic cells [16], natural killer cells [17] and type 1 helper T (Th1) lymphocytes [18,19]. Analysis of clinical data sets shows that co-expression of CXCR3 and its ligand CXCL10 is associated with early metastatic progression and increased metastatic potential in melanoma, colon carcinoma and renal cell carcinoma [25]

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Results

Conclusion