PDF herunterladen
Horm Metab Res 2016; 48(04): 275-279
DOI: 10.1055/s-0035-1565068
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Estradiol Upregulates c-FLIPlong Expression in Anterior Pituitary Cells

G. Jaita
1   Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
,
S. Zárate
1   Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
,
J. Ferraris
1   Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
,
M. F. Gottardo
1   Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
,
G. Eijo
1   Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
,
M. L. Magri
1   Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
,
D. Pisera
1   Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
,
A. Seilicovich
1   Instituto de Investigaciones Biomédicas, Facultad de Medicina, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 26. Juni 2015

accepted 30. September 2015

Publikationsdatum:
13. November 2015 (online)

Auch verfügbar auf
    Lizenzen und Reprints

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
 

  • References

  • 1 Li Z, Sheng M. Caspases in synaptic plasticity. Mol Brain 2012; 5: 15
    CrossrefPubMedGoogle Scholar
  • 2 Yang JK. FLIP as an anti-cancer therapeutic target. Yonsei Med J 2008; 49: 19-27
    CrossrefPubMedGoogle Scholar
  • 3 Ozturk S, Schleich K, Lavrik IN. Cellular FLICE-like inhibitory proteins (c-FLIPs): fine-tuners of life and death decisions. Exp Cell Res 2012; 318: 1324-1331
    CrossrefPubMedGoogle Scholar
  • 4 Golks A, Brenner D, Fritsch C, Krammer PH, Lavrik IN. c-FLIPR a new regulator of death receptor-induced apoptosis. J Biol Chem 2005; 280: 14507-14513
    CrossrefPubMedGoogle Scholar
  • 5 Bagnoli M, Canevari S, Mezzanzanica D. Cellular FLICE-inhibitory protein (c-FLIP) signalling: a key regulator of receptor-mediated apoptosis in physiologic context and in cancer. Int J Biochem Cell Biol 2010; 42: 210-213
    CrossrefPubMedGoogle Scholar
  • 6 Chang DW, Xing Z, Pan Y, Algeciras-Schimnich A, Barnhart BC, Yaish-Ohad S, Peter ME, Yang X. c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. Embo J 2002; 21: 3704-3714
    CrossrefPubMedGoogle Scholar
  • 7 Peter ME. The flip side of FLIP. Biochem J 2004; 382: e1-e3
    CrossrefPubMedGoogle Scholar
  • 8 Abe H, Shibata MA, Otsuki Y. Caspase cascade of Fas-mediated apoptosis in human normal endometrium and endometrial carcinoma cells. Mol Hum Reprod 2006; 12: 535-541
    CrossrefPubMedGoogle Scholar
  • 9 Oh HY, Namkoong S, Lee SJ, Por E, Kim CK, Billiar TR, Han JA, Ha KS, Chung HT, Kwon YG, Lee H, Kim YM. Dexamethasone protects primary cultured hepatocytes from death receptor mediated apoptosis by upregulation of cFLIP. Cell Death Differ 2006; 13: 512-523
    CrossrefPubMedGoogle Scholar
  • 10 Raclaw KA, Heemers HV, Kidd EM, Dehm SM, Tindall DJ. Induction of FLIP expression by androgens protects prostate cancer cells from TRAIL-mediated apoptosis. Prostate 2008; 68: 1696-1706
    CrossrefPubMedGoogle Scholar
  • 11 Nastiuk KL, Krolewski JJ. FLIP-ping out: death receptor signaling in the prostate. Cancer Biol Ther 2008; 7: 1171-1179
    CrossrefPubMedGoogle Scholar
  • 12 Jaita G, Candolfi M, Zaldivar V, Zarate S, Ferrari L, Pisera D, Castro MG, Seilicovich A. Estrogens up-regulate the Fas/FasL apoptotic pathway in lactotropes. Endocrinology 2005; 146: 4737-4744
    CrossrefPubMedGoogle Scholar
  • 13 Jaita G, Zarate S, Ferrari L, Radl D, Ferraris J, Eijo G, Zaldivar V, Pisera D, Seilicovich A. Gonadal steroids modulate Fas-induced apoptosis of lactotropes and somatotropes. Endocrine 2011; 39: 21-27
    CrossrefPubMedGoogle Scholar
  • 14 Candolfi M, Zaldivar V, Jaita G, Seilicovich A. Anterior pituitary cell renewal during the estrous cycle. Front Horm Res 2006; 35: 9-21
    PubMedGoogle Scholar
  • 15 Hashi A, Mazawa S, Kato J, Arita J. Pentobarbital anesthesia during the proestrous afternoon blocks lactotroph proliferation occurring on estrus in female rats. Endocrinology 1995; 136: 4665-4671
    PubMedGoogle Scholar
  • 16 Yin P, Arita J. Proestrous surge of gonadotropin-releasing hormone secretion inhibits apoptosis of anterior pituitary cells in cycling female rats. Neuroendocrinology 2002; 76: 272-282
    CrossrefPubMedGoogle Scholar
  • 17 Kawashima K, Yamakawa K, Takahashi W, Takizawa S, Yin P, Sugiyama N, Kanba S, Arita J. The estrogen-occupied estrogen receptor functions as a negative regulator to inhibit cell proliferation induced by insulin/IGF-1: a cell context-specific antimitogenic action of estradiol on rat lactotrophs in culture. Endocrinology 2002; 143: 2750-2758
    CrossrefPubMedGoogle Scholar
  • 18 Gutierrez S, De Paul AL, Petiti JP, del Valle Sosa L, Palmeri CM, Soaje M, Orgnero EM, Torres AI. Estradiol interacts with insulin through membrane receptors to induce an antimitogenic effect on lactotroph cells. Steroids 2008; 73: 515-527
    CrossrefPubMedGoogle Scholar
  • 19 Zarate S, Jaita G, Zaldivar V, Radl DB, Eijo G, Ferraris J, Pisera D, Seilicovich A. Estrogens exert a rapid apoptotic action in anterior pituitary cells. Am J Physiol Endocrinol Metab 2009; 296: E664-E671
    CrossrefPubMedGoogle Scholar
  • 20 Zaldivar V, Magri ML, Zarate S, Jaita G, Eijo G, Radl D, Ferraris J, Pisera D, Seilicovich A. Estradiol increases the Bax/Bcl-2 ratio and induces apoptosis in the anterior pituitary gland. Neuroendocrinology 2009; 90: 292-300
    CrossrefPubMedGoogle Scholar
  • 21 Seilicovich A. Cell life and death in the anterior pituitary gland: role of oestrogens. J Neuroendocrinol 2010; 22: 758-764
    PubMedGoogle Scholar
  • 22 Lavrik IN. Systems biology of death receptor networks: live and let die. Cell Death Dis 2014; 5: e1259
    CrossrefPubMedGoogle Scholar
  • 23 Boatright KM, Deis C, Denault JB, Sutherlin DP, Salvesen GS. Activation of caspases-8 and 10 by FLIP(L). Biochem J 2004; 382: 651-657
    CrossrefPubMedGoogle Scholar
  • 24 Yu JW, Jeffrey PD, Shi Y. Mechanism of procaspase-8 activation by c-FLIPL. Proc Natl Acad Sci USA 2009; 106: 8169-8174
    CrossrefPubMedGoogle Scholar
  • 25 Subramaniam K, Hirpara JL, Tucker-Kellogg L, Tucker-Kellogg G, Pervaiz S. FLIP: a flop for execution signals. Cancer Lett 2013; 332: 151-155
    CrossrefPubMedGoogle Scholar
  • 26 Ribeiro JR, Freiman RN. Estrogen signaling crosstalk: Implications for endocrine resistance in ovarian cancer. J Steroid Biochem Mol Biol 2014; 143: 160-173
    CrossrefPubMedGoogle Scholar
  • 27 Wu ZB, Li CZ, Zong XY, Su ZP, Zeng YJ, Zhang YZ. Correlation of alternative splicing of the D2 dopamine receptor mRNA and estrogen receptor mRNA in the prolactinomas and gonadotrope tumors. J Neurooncol 2009; 94: 135-139
    CrossrefPubMedGoogle Scholar
  • 28 Nogami H, Hoshino R, Ogasawara K, Miyamoto S, Hisano S. Region-specific expression and hormonal regulation of the first exon variants of rat prolactin receptor mRNA in rat brain and anterior pituitary gland. J Neuroendocrinol 2007; 19: 583-593
    CrossrefPubMedGoogle Scholar
  • 29 Danan-Gotthold M, Golan-Gerstl R, Eisenberg E, Meir K, Karni R, Levanon EY. Identification of recurrent regulated alternative splicing events across human solid tumors. Nucleic Acids Res 2015; 43: 5130-5144
    CrossrefPubMedGoogle Scholar
  • 30 Safa AR. Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy. J Carcinog Mutagen 2013; (Suppl. 06) pii: 003. PubMed PMID: 25379355
    PubMedGoogle Scholar
  • 31 Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K, Liu YC, Karin M. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell 2006; 124: 601-613
    CrossrefPubMedGoogle Scholar
  • 32 Rong W, Wang J, Liu X, Jiang L, Wei F, Zhou H, Han X, Liu Z. 17beta-estradiol attenuates neural cell apoptosis through inhibition of JNK phosphorylation in SCI rats and excitotoxicity induced by glutamate in vitro. Int J Neurosci 2012; 122: 381-387
    CrossrefPubMedGoogle Scholar
  • 33 Watson CS, Campbell CH, Gametchu B. Membrane oestrogen receptors on rat pituitary tumour cells: immuno-identification and responses to oestradiol and xenoestrogens. Exp Physiol 1999; 84: 1013-1022
    CrossrefPubMedGoogle Scholar
  • 34 Schreihofer DA, Stoler MH, Shupnik MA. Differential expression and regulation of estrogen receptors (ERs) in rat pituitary and cell lines: estrogen decreases ERalpha protein and estrogen responsiveness. Endocrinology 2000; 141: 2174-2184
    CrossrefPubMedGoogle Scholar
  • 35 Ben-Jonathan N, Chen S, Dunckley JA, LaPensee C, Kansra S. Estrogen receptor-alpha mediates the epidermal growth factor-stimulated prolactin expression and release in lactotrophs. Endocrinology 2009; 150: 795-802
    CrossrefPubMedGoogle Scholar
  • 36 Eijo G, Gottardo MF, Jaita G, Magri ML, Moreno Ayala M, Zárate S, Candolfi M, Pisera D, Seilicovich A. Lack of oestrogenic inhibition of the NF-κB pathway in pituitary tumour cells. J Neuroendocrinol 2015; 27: 692-701
    CrossrefPubMedGoogle Scholar