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Estrogens Promote Human Testicular Germ Cell Cancer through a Membrane-Mediated Activation of Extracellular Regulated Kinase and Protein Kinase A

Estrogens Promote Human Testicular Germ Cell Cancer through a Membrane-Mediated Activation of Extracellular Regulated Kinase and Protein Kinase A,10.1

Estrogens Promote Human Testicular Germ Cell Cancer through a Membrane-Mediated Activation of Extracellular Regulated Kinase and Protein Kinase A   (Citations: 16)
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Clinical and experimental studies have suggested that estro- gens, the archetype of female hormones, participate in the control of male germ cell proliferation and that fetal exposure to environmental estrogens may contribute to hypofertility and/ortotesticulargermcellcancer.However,theunderlying mechanisms remain to be elucidated. 17-Estradiol (E2) con- jugated to BSA was able to stimulate human testicular semi- noma cell proliferation by triggering a rapid, nongenomic, membrane-mediated activation of ERK1/2 and cAMP-depen- dent protein kinase A (PKA). Both ERK1/2 and PKA partici- pated in this promoting effect. This activation was associated with phosphorylation of the transcription factor cAMP re- sponse element-binding protein and the nuclear factor reti- noblastoma protein. Enhanced proliferation together with ERK activation could be reversed by pertussis toxin, a G pro- tein inhibitor. Estrogen receptors (ERs) in JKT-1 were char- acterized by immunofluorescence, subcellular fractioning, and Western blot. JKT-1 cells did not express ER but ER, which localized to the mitochondria and the nucleus but not to the membrane. Moreover, neither ICI-182,780, a classical ERantagonist,nortamoxifen,aselectiveERmodulator,could reverse the 17-estradiol-BSA-induced promoting effect. Es- trogens contribute to human testicular germ cell cancer pro- liferation by rapid activation of ERK1/2 and PKA through a membrane nonclassical ER. This nongenomic effect repre- sents a new basis for understanding the estrogenic control of spermatogenesis and evaluating the role of fetal exposure to xenoestrogens during malignant transformation of testicular germ stem cells. (Endocrinology 149: 565-573, 2008)
Journal: Endocrinology , vol. 149, no. 2, pp. 565-573, 2007
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