Estrogen receptor beta (ERβ) produces autophagy and necroptosis in human seminoma cell line through the binding of the Sp1 on the phosphatase and tensin homolog 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.

Cytoskeleton Modifications and Autophagy Induction in TCam-2 Seminoma Cells Exposed to Simulated Microgravity

“…Autophagy induced in TCam-2 cells by Estrogen exposure through ER β activation was recently reported [59]. Herein we reported, for the first time, autophagy induced in TCam-2 cells by a mechanical cue (or, more precisely, by a removal of a mechanical stimulus) instead of a biochemical one.…”

In VitroChronic Administration of ERbeta Selective Ligands and Prostate Cancer Cell Growth: Hypotheses on the Selective Role of 3beta-Adiol in AR-Positive RV1 Cells

“…Moreover, a partial loss of PTEN is extremely frequent in human primary cancers, particularly in PC, making the possibility to increase or maintain appropriate PTEN levels, an important target for chemoprevention. The ability of ERbeta activation to increase PTEN expression in cancer cells has been demonstrated by some authors in PC [45] and in other cancer models [42, 46, 47], but, to our knowledge, such effect of ERbeta activation over a long time frame has never been evaluated. To this regard, our results demonstrated that PTEN expression levels are not influenced by the activation of the endogenous ERbeta by 3beta-Adiol, as well as by 8beta-VE2, whereas DPN seems to display a slight activity from 5 weeks of treatment onward, which however influences cell proliferation only at the end of the chronic treatment (T12).…”

Ras and autophagy in cancer development and therapy

“…These include Ras (which will be discussed below), EGFR and HER2/Neu [19], p53 [20], BCR-Abl [21, 22], PTEN [23, 24], Myc [25, 26], NF-κB [27] and estrogen receptor [28]. Consequently, anti-cancer drugs targeting these proteins were also shown to modulate autophagy [20, 29].…”