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 are the most common tumor in male and the least studied. We focused on human seminoma using the TCAM2 cell line. Through ERβ, 10 nM estradiol (E2) was able to induce PTEN gene expression and promoter transactivation. Transient transfections, ChIP and EMSA assays evidenced the 5'-flanking region of PTEN gene promoter E2-responsive. The ERβ binding to the Sp1 on PTEN promoter decreased cell survival. The presence of ERβ or PTEN is necessary to induce the loss of cell survival upon E2, addressing their cooperation in this action. pAKT and AKT expression decreased under E2 and DPN, while known apoptotic markers appeared to be unchanged. The PI3K/AKT pathway inhibition also leads to autophagy: E2 and DPN enhanced the expression of autophagy-related markers such as PI3III, Beclin 1, AMBRA and UVRAG. MDC and TEM assays confirmed E2-induced autophagy. The absence of DNA fragmentation, caspase 9 and PARP1 cleavages suggested that necroptosis and/or parthanatos may occur. FACS analysis, LDH assay and RIP1 expression attested this hypothesis. Our study reveals a unique mechanism through which ERβ/PTEN signaling induces cell death in TCAM2 by autophagy and necroptosis. These data, supporting estrogen-dependency of human seminoma, propose ERβ ligands for therapeutic use in the treatment of this pathological condition.

• Authors: Carmela Guido, Salvatore Panza, Marta Santoro, Paola Avena, Maria Luisa Panno, Ida Perrotta, Francesca Giordano, Ivan Casaburi, Stefania Catalano, Francesca De Amicis, Federica Sotgia, Michael P Lisanti, Sebastiano Andò, Saveria Aquila
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 11 Issue 15 Pg. 2911-21 (Aug 01 2012) ISSN: 1551-4005 [Electronic] United States
• PMID: 22810004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AMBRA1 protein, human
• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Estrogen Receptor beta
• Membrane Proteins
• Phosphoinositide-3 Kinase Inhibitors
• Tumor Suppressor Proteins
• UVRAG protein, human
• Estradiol
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Proto-Oncogene Proteins c-akt
• PTEN Phosphohydrolase
• PTEN protein, human
• Caspase 9

Topics

• Adaptor Proteins, Signal Transducing (biosynthesis)
• Apoptosis Regulatory Proteins (biosynthesis)
• Autophagy
• Beclin-1
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cell Survival
• Estradiol
• Estrogen Receptor beta (metabolism)
• Humans
• Male
• Membrane Proteins (biosynthesis)
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (biosynthesis)
• Phosphoinositide-3 Kinase Inhibitors
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, biosynthesis, genetics)
• Seminoma (genetics, metabolism, pathology)
• Signal Transduction (genetics)
• Testicular Neoplasms (genetics)
• Transcription, Genetic
• Tumor Suppressor Proteins (biosynthesis)