Abstract
Anterior pituitary cell turnover depends on a tight balance between proliferation
and apoptosis. We have previously shown that estrogens sensitize anterior pituitary
cells to pro-apoptotic stimuli. c-FLIP (cellular-FLICE-inhibitory-protein) isoforms
are regulatory proteins of apoptosis triggered by death receptors. c-FLIPshort isoform competes with procaspase-8 inhibiting its activation. However, c-FLIPlong isoform may have a pro- or anti-apoptotic function depending on its expression level.
In the present study, we explored whether estrogens modulate c-FLIP expression in
anterior pituitary cells from ovariectomized (OVX) rats and in GH3 cells, a somatolactotrope
cell line. Acute administration of 17β-estradiol to OVX rats increased c-FLIPlong expression in the anterior pituitary gland without changing c-FLIPshort expression as assessed by Western blot. Estradiol in vitro also increased c-FLIPlong expression in anterior pituitary cells but not in GH3 cells. As determined by flow
cytometry, the percentage of anterior pituitary cells expressing c-FLIP was higher
than in GH3 cells. However, c-FLIP fluorescence intensity in GH3 cells was higher
than in anterior pituitary cells. FasL increased the percentage of TUNEL-positive
GH3 cells incubated either with or without estradiol suggesting that the pro-apoptotic
action of Fas activation is estrogen-independent. Our results show that unlike what
happens in nontumoral pituitary cells, estrogens do not modulate either c-FLIPlong expression or FasL-induced apoptosis in GH3 cells. The stimulatory effect of estradiol
on c-FLIPlong expression could be involved in the sensitizing effect of this steroid to apoptosis
in anterior pituitary cells. The absence of this estrogenic action in tumor pituitary
cells could be involved in their tumor-like behavior.
Key words
FasL - estrogens - apoptosis - pituitary - GH3
