Estrogen Receptor beta produces cell death in TCAM2 human seminoma cell line binding through Sp1 on the phosphatase and tensin homologue deleted from chromosome 10 (PTEN) promoter gene

Abstract

Testicular germ cell tumors of adults and adolescents (TGCTs) are the most common tumor in male. We focused on seminoma, by using the TCAM‐2 cell line, containing typical features of human seminoma. As both PTEN and estradiol (E2) appear to have an important role in the testis development and function, we evaluated a potential action of E2 on PTEN promoter gene. Increasing E2 concentrations were able to induce PTEN gene expression and transactivation. By transient trasfections, ChIP and EMSA assays, we evidenced the 5′‐flanking region of human PTEN gene important for E2‐responsiveness, the ERβ binding to the Sp1 regulates PTEN activity. The functional significance of the link between ERβ/PTEN was tested on cell viability, an increase in cell death was observed. The effect was abolished by trasfecting the TCAM2 cells with negative dominant of ERβ or by using mithramycin, confirming that the E2‐induced effect involves both ERβ and Sp1. E2 decreases AKT, while FHKR and BAD increased. The PI3K/AKT pathway is shared to the autophagy, and E2 increased autophagy‐related markers such as PI3III, Beclin 1, AMBRA and UVRAG. Our study suggesting a tumor suppressor role for the ERβ in human seminoma, indicates that the E2 induces cell death in TCAM2 mainly through autophagy, supporting estrogen‐dependency of human seminoma and candidating the ERβ‐ligands for a therapeutic use in the treatment of this pathological condition.