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

Estrogen receptor a (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 ER alpha 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 ER alpha in OSCC cells and the mechanism underlying ERa activation. Immunochemical analyses in benign (n=11) and malignant (n=21) lesions of the oral cavity showed that ER alpha immunoreactivity was observed in 43% (9/21) of malignant lesions, whereas none of benign lesions showed ER alpha immunoreactivity. The ER alpha 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 ER alpha expression caused reduced cell growth. Interestingly, the expression and activity of focal adhesion kinase (FAK) were associated with the phosphorylation of ER alpha at serine 118 in OSCC cells. Elevated expression of FAK in the slow-growing SCC25 cells caused increases in ER alpha phosphorylation, transcriptional activity, and cell growth rate, whereas knockdown of FAK expression in the rapid-growing OECM-1 cells led to reduced ER alpha phosphorylation and activity and retarded cell growth. Inhibition of the activity of protein kinase B (AKT), but not ERK, abolished FAK-promoted ER alpha phosphorylation. These results suggest that OSCC cells expressed functional ER alpha, whose activity can be enhanced by FAK/AKT signaling, and this was critical for promoting cell growth. Thus, FAK and ERa can serve as the therapeutic targets for the treatment of OSCC.