Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4

Abstract

BackgroundIncreasing evidence indicates that the interaction between the CXC chemokine receptor-4 (CXCR4) and its ligand CXCL12 is critical in the process of metastasis that accounts for more than 90% of cancer-related deaths. Thus, novel agents that can downregulate the CXCR4/CXCL12 axis have therapeutic potential in inhibiting cancer metastasis.MethodsIn this report, we investigated the potential of an agent, plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), for its ability to modulate CXCR4 expression and function in various tumor cells using Western blot analysis, DNA binding assay, transient transfection, real time PCR analysis, chromatin immunoprecipitation, and cellular migration and invasion assays.ResultsWe found that plumbagin downregulated the expression of CXCR4 in breast cancer cells irrespective of their HER2 status. The decrease in CXCR4 expression induced by plumbagin was not cell type-specific as the inhibition also occurred in gastric, lung, renal, oral, and hepatocellular tumor cell lines. Neither proteasome inhibition nor lysosomal stabilization had any effect on plumbagin-induced decrease in CXCR4 expression. Detailed study of the underlying molecular mechanism(s) revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, inhibition of NF-κB activation, and suppression of chromatin immunoprecipitation activity. In addition, using a virtual, predictive, functional proteomics-based tumor pathway platform, we tested the hypothesis that NF-κB inhibition by plumbagin causes the decrease in CXCR4 and other metastatic genes. Suppression of CXCR4 expression by plumbagin was found to correlate with the inhibition of CXCL12-induced migration and invasion of both breast and gastric cancer cells.ConclusionsOverall, our results indicate, for the first time, that plumbagin is a novel blocker of CXCR4 expression and thus has the potential to suppress metastasis of cancer.

Suppressive Effects of Plumbagin on Invasion and Migration of Breast Cancer Cells via the Inhibition of STAT3 Signaling and Down-regulation of Inflammatory Cytokine Expressions

“…Previous studies have shown that plumbagin can inhibit tumor cell proliferation in vitro by inducing apoptosis and autophagy of breast neoplasm cells (13) and the invasion of prostate cancer cells (14). Recent studies have also demonstrated that plumbagin can inhibits osteoclastogenesis and reduces human breast cancerinduced osteolytic bone metastasis (16)(17)(18), however, more in vivo evidence need to be supplemented and the relevant mechanisms still remain to be investigated. Therefore, the aim of this study is to investigate whether there are any suppressive effects of plumbagin on the invasion and migration of human breast cancer MDA-MB-231SArfp cells and to explore potential functional mechanisms.…”

Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor γ Activation Pathway in Gastric Cancer

“…A wound was created using a pipette tip and each well was rinsed with PBS to remove detached cells. The cells were pretreated with GW9662, a pharmacological PPAR-␥ specific inhibitor for 2 h, followed by incubation with IH for 8 h. The microscopic observation of the cells was recorded as described previously (35).…”

Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH

“…PLB has been shown to exert anticancer activities against a wide variety of tumour cells, including breast cancer and lung cancer, in which NFAT is activated [4,[12][13][14][15]. However, the mechanisms accounting for PLB anticancer effects remain unknown.…”