Regulation of estrogen receptor α function in oral squamous cell carcinoma cells by FAK signaling.

Abstract

Estrogen receptor α (ERA) is a DNA-binding transcription factor that plays an important role in the regulation of cell growth. Previous studies indicated that the expression of ERα in cell lines and tumors derived from oral squamous cell carcinoma (OSCC). The aim of this study was to examine the activity and function of ERα in OSCC cells and the mechanism underlying ERα activation. Immunochemical analyses in benign (n=11) and malignant (n=21) lesions of the oral cavity showed that ERα immunoreactivity was observed in 43% (9/21) of malignant lesions, whereas none of benign lesions showed ERα immunoreactivity. The ERα expression was also found in three OSCC cell lines and its transcriptional activity was correlated with cell growth. Addition of estradiol stimulated cell growth, whereas treatment of tamoxifen or knockdown of ERα expression caused reduced cell growth. Interestingly, the expression and activity of focal adhesion kinase (FAK) were associated with the phosphorylation of ERα at serine 118 in OSCC cells. Elevated expression of FAK in the slow-growing SCC25 cells caused increases in ERα phosphorylation, transcriptional activity, and cell growth rate, whereas knockdown of FAK expression in the rapid-growing OECM-1 cells led to reduced ERα phosphorylation and activity and retarded cell growth. Inhibition of the activity of protein kinase B (AKT), but not ERK, abolished FAK-promoted ERα phosphorylation. These results suggest that OSCC cells expressed functional ERα, whose activity can be enhanced by FAK/AKT signaling, and this was critical for promoting cell growth. Thus, FAK and ERα can serve as the therapeutic targets for the treatment of OSCC.