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. 2020 Mar 26;10(4):502.
doi: 10.3390/biom10040502.

Luteolin-7-O-Glucoside Inhibits Oral Cancer Cell Migration and Invasion by Regulating Matrix Metalloproteinase-2 Expression and Extracellular Signal-Regulated Kinase Pathway

Bharath Kumar Velmurugan  1 , Jen-Tsun Lin  2   3 , B Mahalakshmi  4 , Yi-Ching Chuang  5 , Chia-Chieh Lin  5 , Yu-Sheng Lo  5 , Ming-Ju Hsieh  5   6   7   8 , Mu-Kuan Chen  9
Affiliations

Luteolin-7-O-Glucoside Inhibits Oral Cancer Cell Migration and Invasion by Regulating Matrix Metalloproteinase-2 Expression and Extracellular Signal-Regulated Kinase Pathway

Bharath Kumar Velmurugan et al. Biomolecules. .

Abstract

Oral squamous cell carcinoma is the sixth most common type of cancer globally, which is associated with high rates of cancer-related deaths. Metastasis to distant organs is the main reason behind worst prognostic outcome of oral cancer. In the present study, we aimed at evaluating the effects of a natural plant flavonoid, luteolin-7-O-glucoside, on oral cancer cell migration and invasion. The study findings showed that in addition to preventing cell proliferation, luteolin-7-O-glucoside caused a significant reduction in oral cancer cell migration and invasion. Mechanistically, luteolin-7-O-glucoside caused a reduction in cancer metastasis by reducing p38 phosphorylation and downregulating matrix metalloproteinase (MMP)-2 expression. Using a p38 inhibitor, SB203580, we proved that luteolin-7-O-glucoside exerts anti-migratory effects by suppressing p38-mediated increased expression of MMP-2. This is the first study to demonstrate the luteolin-7-O-glucoside inhibits cell migration and invasion by regulating MMP-2 expression and extracellular signal-regulated kinase pathway in human oral cancer cell. The study identifies luteolin-7-O-glucoside as a potential anti-cancer candidate that can be utilized clinically for improving oral cancer prognosis.

Keywords: Luteolin-7-O-glucoside; MMP-2; invasion; migration; oral cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cytotoxicity of Luteolin-7-O-glucosidein human oral cancer cells. (a) FaDu, (b) HSC-3, and (c) CA9-22 cell lines were treated with various concentrations (0, 10, 20, and 40 μM) of luteolin-7-O-glucoside for 24 h, and the cell viability was determined by MTT assay. The values are represented as mean ± SD of at least three independent experiments. *p < 0.05, compared with the control group.
Figure 2
Figure 2
Luteolin-7-O-glucoside inhibits cell motility inhuman oral cancer cells. The effect of luteolin-7-O-glucoside treatment on cell motility was analyzed in (a,b) FaDu, (c,d) HSC-3, and (e,f) CA9-22 cells. The values are represented as mean ± SD of at least three independent experiments. *p < 0.05, compared with the control group.
Figure 3
Figure 3
Luteolin-7-O-glucoside inhibits cell migration and invasion inhuman oral cancer cells. The effect of luteolin-7-O-glucoside treatment on cell migration (a) and invasion (c) was measured using trans-well assay in FaDu, HSC-3, and CA9-22 cells. The percentages of cells in migration and invasion assays are shown in (b) and (d), respectively. The values are represented as mean ± SD of at least three independent experiments. *p < 0.05, compared with the control group.
Figure 4
Figure 4
Luteolin-7-O-glucoside reduces the protein expression of matrix metalloproteinase (MMP)-2 in human oral cancer cells. The protein expression of MMP-2 was determined using Western blot in (a) HSC-3 and (c) FaDu cells. The quantitative results are shown in (b) and (d). The values are represented as mean± SD of at least three independent experiments. *p < 0.05, compared with the control group.
Figure 5
Figure 5
Luteolin-7-O-glucoside inhibits p38 pathway in human oral cancer cells. The phosphorylation as well as the total protein expressions of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase 1/2 (JNK1/2), and p38 were measured after luteolin-7-O-glucoside treatment for 24 h in (a,b) HSC-3 and (c,d) FaDu cell lines. The values are represented as mean ± SD of at least three independent experiments. *p < 0.05, compared with the control group.
Figure 6
Figure 6
Effect of SB203580 and luteolin-7-O-glucoside co-treatment on MMP-2 protein expression in HSC-3 and FaDu cell lines. (a,b) HSC-3 and (c,d) FaDu cell lines were pre-treated with SB203580 for 1h, followed by treatment with Luteolin-7-O-glucoside for 24 h. Next, the culture medium was subjected to western blot assay to determine the MMP-2 expression. The values are represented as mean ± SD of at least three independent experiments. *p < 0.05, compared to the control group; #p < 0.05, compared to the luteolin-7-O-glucoside treated group.
Figure 7
Figure 7
Effect of SB203580 and luteolin-7-O-glucoside co-treatment on cell motility in HSC-3 and FaDu cell lines. The cell motility was measured using wound healing assay after the co-treatment with SB203580 and luteolin-7-O-glucosidein (a,b) HSC-3 and (c,d) FaDu cell lines. The values are represented as mean ± SD of at least three independent experiments. *p < 0.05, compared to the control group; #p < 0.05, compared to the luteolin-7-O-glucoside treated group.
Figure 8
Figure 8
Effect of SB203580 and luteolin-7-O-glucoside co-treatment on cell migration in HSC-3 and FaDu cell lines. The cell migration (a) was measured using trans-well assay after the co-treatment with SB203580 and luteolin-7-O-glucosidein HSC-3 and FaDu cell lines. The quantitative results are shown for (b) HSC-3 and (c) FaDu cells. The values are represented as mean ± SD of at least three independent experiments. *p < 0.05, compared to the control group; #p < 0.05, compared to the luteolin-7-O-glucoside treated group.
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