Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells

A. Chimento, I. Casaburi, M. Bartucci, M. Patrizii, R. Dattilo, P. Avena, S. Andò, V. Pezzi, R. Sirianni

Research output: Contribution to journalArticle

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Abstract

We have previously shown that estrogens binding to estrogen receptor (ER) a increase proliferation of Leydig tumor cells. Estrogens can also bind to G protein-coupled ER (GPER) and activation of this receptor can either increase or decrease cell proliferation of several tumor types. The aim of this study was to investigate GPER expression in R2C rat tumor Leydig cells, evaluate effects of its activation on Leydig tumor cell proliferation and define the molecular mechanisms triggered in response to its activation. R2C cells express GPER and its activation, using the specific ligand G-1, is associated with decreased cell proliferation and initiation of apoptosis. Apoptosis after G-1 treatment was asserted by appearance of DNA condensation and fragmentation, decrease in Bcl-2 and increase in Bax expression, cytochrome c release, caspase and poly (ADP-ribose) polymerase-1 (PARP-1) activation. These effects were dependent on GPER activation because after silencing of the gene, using a specific small interfering RNA, cyt c release, PARP-1 activation and decrease in cell proliferation were abrogated. These events required a rapid, however, sustained extracellular regulated kinase 1/2 activation. G-1 was able to decrease the growth of R2C xenograft tumors in CD1 nude mice while increasing the number of apoptotic cells. In addition, in vivo administration of G-1 to male CD1 mice did not cause any alteration in testicular morphology, while cisplatin, the cytotoxic drug currently used for the therapy of Leydig tumors, severely damaged testicular structure, an event associated with infertility in cisplatin-treated patients. These observations indicate that GPER targeting for the therapy of Leydig cell tumor may represent a good alternative to cisplatin to preserve fertility in Leydig tumor patients.

Original languageEnglish (US)
Article numbere747
JournalCell Death and Disease
Volume4
Issue number8
DOIs
StatePublished - Aug 2013

Fingerprint

Leydig Cell Tumor
GTP-Binding Proteins
Apoptosis
Cell Proliferation
Cisplatin
Neoplasms
Estrogen Receptors
Estrogens
Gene Silencing
DNA Fragmentation
Caspases
G-Protein-Coupled Receptors
Cytochromes c
Heterografts
Nude Mice
Infertility
Small Interfering RNA
Fertility
Phosphotransferases
Therapeutics

Keywords

  • Apoptosis
  • GPER
  • Leydig cell tumor

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

Chimento, A., Casaburi, I., Bartucci, M., Patrizii, M., Dattilo, R., Avena, P., ... Sirianni, R. (2013). Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells. Cell Death and Disease, 4(8), [e747]. https://doi.org/10.1038/cddis.2013.275

Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells. / Chimento, A.; Casaburi, I.; Bartucci, M.; Patrizii, M.; Dattilo, R.; Avena, P.; Andò, S.; Pezzi, V.; Sirianni, R.

In: Cell Death and Disease, Vol. 4, No. 8, e747, 08.2013.

Research output: Contribution to journalArticle

Chimento, A, Casaburi, I, Bartucci, M, Patrizii, M, Dattilo, R, Avena, P, Andò, S, Pezzi, V & Sirianni, R 2013, 'Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells', Cell Death and Disease, vol. 4, no. 8, e747. https://doi.org/10.1038/cddis.2013.275
Chimento, A. ; Casaburi, I. ; Bartucci, M. ; Patrizii, M. ; Dattilo, R. ; Avena, P. ; Andò, S. ; Pezzi, V. ; Sirianni, R. / Selective GPER activation decreases proliferation and activates apoptosis in tumor Leydig cells. In: Cell Death and Disease. 2013 ; Vol. 4, No. 8.
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