Berberine suppresses in vitro migration and invasion of human SCC-4 tongue squamous cancer cells through the inhibitions of FAK, IKK, NF-κB, u-PA and MMP-2 and -9
Introduction
It was reported that over 300,000 cases of oral and oropharyngeal cancer occur per year and occurrence is higher in males than in females [1]. Oral cancer cases and deaths are associated with individual predisposition such as specific genetic characteristics but lifestyle factors such as tobacco/bidi smoking, [2], [3] betel quid, [4] heavy alcohol drinking, [5] micronutrient deficiency [6] and human papillomavirus infection [7] play a role. Two or more of these factors can increase the risk of oral cancer [8], [9]. The betel quid chewing for example has a strong association with the occurrence of oral cancer in Taiwan. Based on reports from the People Health Bureau of Taiwan, approximately 6 per 100,000 die annually of oral cancer in Taiwan and oral cancer has been elevated to be the fourth most frequent cause of cancer death among males in Taiwan. Treatment options for oral cancer such as surgery, radiotherapy and chemotherapy have not been satisfactory. Therefore, it is important to identify new agents and novel targets for the treatment of oral cancer.
Berberine, a natural alkaloid found in natural plants, is anti-bacterial, [10] anti-oxidative, [11] anti-inflammatory, [12] anti-carcinogenic activity [13] and exerts anti-metastatic properties in non-small lung cancer cells [14]. It was reported that berberine suppressed cyclooxygenase-2 transcriptional and activator protein-1 activity in human colon cancer cells [15], [16] and DNA topoisomerase II [17]. Berberine induced cytotoxic activity in human leukemia U937 and murine melanoma B16 cells, [18] human prostate cancer cells [10] and human epidermoid carcinoma A431 cells [19].
In our laboratory, we have reported that berberine inhibited N-acetyltransferase activity in human colon tumor cells [20] and induced apoptosis in human oropharyngeal cancer HSC-3 cells [21] and inhibited rat vascular smooth muscle cell proliferation and migration in vitro[22]. Inhibition of berberine on the induction of migration and invasion in human tongue cancer cells has not been reported. The purpose of this study was to investigate effects of berberine on the induction of migration and invasion in human SCC-4 tongue squamous carcinoma cells. We show that berberine inhibited the migration and invasion of SCC-4 cells through the inhibition of MMP-2 and -9.
Section snippets
Materials and chemicals
Berberine, dimethyl sulfoxide (DMSO), trypan blue and triton X-100, pyruvate, penicillin G and streptomycin were obtained from Sigma Chemical. (St. Louis, MO, USA). Anti-MMP-2, anti-MMP-9, anti-FAK, anti-u-PA, anti-p-p38, anti-p-JNK, anti-p-ERK, anti-IKK, anti-NF-κB and anti-IκB were purchased from Santa Cruz Biotechnology. Materials and chemicals for electrophoresis were obtained from BioRad.
Cell culture
The human SCC-4 tongue squamous carcinoma cell line was purchased from the Food Industry Research and
Berberine decreased the percentages of viable SCC-4 cells
Effects of berberine on the percentage of viable SCC-4 cells were examined and quantified by trypan blue exclusion and flow cytometric analysis. It can be seen in Fig. 1 that berberine induced cytotoxicity and decreased the percentage of viable cells from 40% to 52% (P < 0.001) of 62.5 and 125 μM berberine at 48 h treatment but at 24 h treatment of berberin, only 125 μM induced a significant decrease of viable cells.
Berberine inhibited the migration of SCC-4 cells in vitro
Effects of berberine on cell migration were investigated using a wound-healing assay
Discussion
The anti-cancer effect of berberine has been well documented in many different types of human cancers [11], [12], [14], [15], [16], [17], [18], [19], [26]. In this study, our results demonstrated that berberine decreased the percentage of human SCC-4 tongue cancer viable cells in a dose-dependent manner, which is in agreement with our previous studies. However, actions of berberine on migration and invasion of SCC-4 cells and the associated signaling pathways have not been reported. In this
Conflict of Interest Statement
None declared.
Acknowledgments
This work was supported by Grant CMU97-094 from China Medical University, Taiwan and NIH grants AG-23524 and AG-18357, USA.
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