Activation of telomerase by seminal plasma in malignant and normal cervical epithelial cells

Abstract

Seminal fluids are involved in the development of cervical cancer but the underlying mechanism is unclear. Because cellular transformation requires telomerase activation by expression of the telomerase reverse transcriptase (hTERT) gene, we examined the role of seminal fluids in telomerase activation. Significantly elevated hTERT mRNA and telomerase activity were observed in cervical cell lines (HeLa, SiHa and Caski) treated with seminal plasma. Normal cervical epithelial cells expressed minimal levels of hTERT mRNA and telomerase activity, and seminal plasma substantially enhanced both expression and activity. The hTERT promoter activity was similarly increased in seminal plasma-treated HeLa cells and this effect was closely correlated with increased Sp1 expression and binding to the hTERT promoter. Cyclooxygenase-2 (COX-2) was simultaneously increased in HeLa cells exposed to seminal plasma, and blockade of COX-2 induction abolished seminal plasma stimulation of the hTERT promoter activity, hTERT expression and telomerase activity. Prostaglandin E2 (PGE2) mimics the effect of seminal plasma, stimulating Sp1 expression, enhancing Sp1 occupancy on the hTERT promoter and promoter activity. Moreover, tumour growth was robustly enhanced when HeLa cells together with seminal plasma were injected into nude-mice. Taken together, seminal plasma stimulates COX-2-PGE2-Sp1-dependent hTERT transcription, which provides insights into the putative mechanism underlying telomerase activation in cervical epithelial and cancer cells.