Abstract
Prolactinomas are increasingly viewed as a “problem of signal transduction.” Consequently, the identification of factors and signaling pathways that control lactotrope cell turnover is needed in order to encourage new therapeutic developments. We have previously shown that prolactin (PRL) acts as a proapoptotic and antiproliferative factor on lactotropes, maintaining anterior pituitary cell homeostasis, which contrasts with the classical antiapoptotic and/or proliferative actions exerted by PRL in most other target tissues. We aimed to investigate the PRLR-triggered signaling pathways mediating these nonclassical effects of PRL in the pituitary. Our results suggest that (i) the PRLR/Jak2/STAT5 pathway is constitutively active in GH3 cells and contributes to PRL-induced apoptosis by increasing the Bax/Bcl-2 ratio, (ii) PRL inhibits ERK1/2 and Akt phosphorylation, thereby contributing to its proapoptotic effect, and (iii) the PI3K/Akt pathway participates in the PRL-mediated control of lactotrope proliferation. We hypothesize that the alteration of PRL actions in lactotrope homeostasis due to the dysregulation of any of the mechanisms of actions described above may contribute to the pathogenesis of prolactinomas.
References
1.
Schuff
KG
, Hentges
ST
, Kelly
MA
, Binart
N
, Kelly
PA
, Iuvone
PM
, et al.. Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms
. J Clin Invest
. 2002
Oct
;110
(7
):973
–81
.
[PubMed]
0021-97382.
Ferraris
J
, Boutillon
F
, Bernadet
M
, Seilicovich
A
, Goffin
V
, Pisera
D
. Prolactin receptor antagonism in mouse anterior pituitary: effects on cell turnover and prolactin receptor expression
. Am J Physiol Endocrinol Metab
. 2012
Feb
;302
(3
):E356
–64
.
[PubMed]
0193-18493.
Ferraris
J
, Zárate
S
, Jaita
G
, Boutillon
F
, Bernadet
M
, Auffret
J
, et al.. Prolactin induces apoptosis of lactotropes in female rodents
. PLoS One
. 2014
May
;9
(5
):e97383
.
[PubMed]
1932-62034.
Clevenger
CV
, Furth
PA
, Hankinson
SE
, Schuler
LA
. The role of prolactin in mammary carcinoma
. Endocr Rev
. 2003
Feb
;24
(1
):1
–27
.
[PubMed]
0163-769X5.
Costanza
M
, Binart
N
, Steinman
L
, Pedotti
R
. Prolactin: a versatile regulator of inflammation and autoimmune pathology
. Autoimmun Rev
. 2015
Mar
;14
(3
):223
–30
.
[PubMed]
1568-99726.
Das
R
, Vonderhaar
BK
. Activation of raf-1, MEK, and MAP kinase in prolactin responsive mammary cells
. Breast Cancer Res Treat
. 1996
;40
(2
):141
–9
.
[PubMed]
0167-68067.
Goffin
V
, Touraine
P
. The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications
. Expert Opin Ther Targets
. 2015
;19
(9
):1229
–44
.
[PubMed]
1472-82228.
Llovera
M
, Pichard
C
, Bernichtein
S
, Jeay
S
, Touraine
P
, Kelly
PA
, et al.. Human prolactin (hPRL) antagonists inhibit hPRL-activated signaling pathways involved in breast cancer cell proliferation
. Oncogene
. 2000
Sep
;19
(41
):4695
–705
.
[PubMed]
0950-92329.
Sackmann-Sala
L
, Goffin
V
. Prolactin-induced prostate tumorigenesis
. Adv Exp Med Biol
. 2015
;846
:221
–42
.
[PubMed]
0065-259810.
DeVito
WJ
, Okulicz
WC
, Stone
S
, Avakian
C
. Prolactin-stimulated mitogenesis of cultured astrocytes
. Endocrinology
. 1992
May
;130
(5
):2549
–56
.
[PubMed]
0013-722711.
Larsen
CM
, Grattan
DR
. Prolactin, neurogenesis, and maternal behaviors
. Brain Behav Immun
. 2012
Feb
;26
(2
):201
–9
.
[PubMed]
0889-159112.
Buckley
AR
. Prolactin, a lymphocyte growth and survival factor
. Lupus
. 2001
;10
(10
):684
–90
.
[PubMed]
0961-203313.
Castilla
A
, García
C
, Cruz-Soto
M
, Martínez de la Escalera
G
, Thebault
S
, Clapp
C
. Prolactin in ovarian follicular fluid stimulates endothelial cell proliferation
. J Vasc Res
. 2010
;47
(1
):45
–53
.
[PubMed]
1018-117214.
Clevenger
CV
, Plank
TL
. Prolactin as an autocrine/paracrine factor in breast tissue
. J Mammary Gland Biol Neoplasia
. 1997
Jan
;2
(1
):59
–68
.
[PubMed]
1083-302115.
Ben-Jonathan
N
, LaPensee
CR
, LaPensee
EW
. What can we learn from rodents about prolactin in humans
. Endocr Rev
. 2008
Feb
;29
(1
):1
–41
.
[PubMed]
0163-769X16.
Binart
N
, Bachelot
A
, Bouilly
J
. Impact of prolactin receptor isoforms on reproduction
. Trends Endocrinol Metab
. 2010
Jun
;21
(6
):362
–8
.
[PubMed]
1043-276017.
Bole-Feysot
C
, Goffin
V
, Edery
M
, Binart
N
, Kelly
PA
. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice
. Endocr Rev
. 1998
Jun
;19
(3
):225
–68
.
[PubMed]
0163-769X18.
Aksamitiene
E
, Achanta
S
, Kolch
W
, Kholodenko
BN
, Hoek
JB
, Kiyatkin
A
. Prolactin-stimulated activation of ERK1/2 mitogen-activated protein kinases is controlled by PI3-kinase/Rac/PAK signaling pathway in breast cancer cells
. Cell Signal
. 2011
Nov
;23
(11
):1794
–805
.
[PubMed]
0898-656819.
Shemanko
CS
. Prolactin receptor in breast cancer: marker for metastatic risk
. J Mol Endocrinol
. 2016
Nov
;57
(4
):R153
–65
.
[PubMed]
0952-504120.
Freeman
ME
, Kanyicska
B
, Lerant
A
, Nagy
G
. Prolactin: structure, function, and regulation of secretion
. Physiol Rev
. 2000
Oct
;80
(4
):1523
–631
.
[PubMed]
0031-933321.
Bernard
V
, Young
J
, Chanson
P
, Binart
N
. New insights in prolactin: pathological implications
. Nat Rev Endocrinol
. 2015
May
;11
(5
):265
–75
.
[PubMed]
1759-502922.
Chipoy
C
, Brounais
B
, Trichet
V
, Battaglia
S
, Berreur
M
, Oliver
L
, et al.. Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53
. Oncogene
. 2007
Oct
;26
(46
):6653
–64
.
[PubMed]
0950-923223.
Stankiewicz
TR
, Loucks
FA
, Schroeder
EK
, Nevalainen
MT
, Tyler
KL
, Aktories
K
, et al.. Signal transducer and activator of transcription-5 mediates neuronal apoptosis induced by inhibition of Rac GTPase activity
. J Biol Chem
. 2012
May
;287
(20
):16835
–48
.
[PubMed]
0021-925824.
Bernichtein
S
, Kayser
C
, Dillner
K
, Moulin
S
, Kopchick
JJ
, Martial
JA
, et al.. Development of pure prolactin receptor antagonists
. J Biol Chem
. 2003
Sep
;278
(38
):35988
–99
.
[PubMed]
0021-925825.
Untergasser
A
, Cutcutache
I
, Koressaar
T
, Ye
J
, Faircloth
BC
, Remm
M
, et al.. Primer3—new capabilities and interfaces
. Nucleic Acids Res
. 2012
Aug
;40
(15
):e115
.
[PubMed]
0305-104826.
Dagvadorj
A
, Collins
S
, Jomain
JB
, Abdulghani
J
, Karras
J
, Zellweger
T
, et al.. Autocrine prolactin promotes prostate cancer cell growth via Janus kinase-2-signal transducer and activator of transcription-5a/b signaling pathway
. Endocrinology
. 2007
Jul
;148
(7
):3089
–101
.
[PubMed]
0013-722727.
Ma
FY
, Anderson
GM
, Gunn
TD
, Goffin
V
, Grattan
DR
, Bunn
SJ
. Prolactin specifically activates signal transducer and activator of transcription 5b in neuroendocrine dopaminergic neurons
. Endocrinology
. 2005
Dec
;146
(12
):5112
–9
.
[PubMed]
0013-722728.
Gottardo
MF
, Moreno Ayala
M
, Ferraris
J
, Zárate
S
, Pisera
D
, Candolfi
M
, et al.. Humanin inhibits apoptosis in pituitary tumor cells through several signaling pathways including NF-κB activation
. J Cell Commun Signal
. 2017
Dec
;11
(4
):329
–40
.
[PubMed]
1873-960129.
Radl
DB
, Ferraris
J
, Boti
V
, Seilicovich
A
, Sarkar
DK
, Pisera
D
. Dopamine-induced apoptosis of lactotropes is mediated by the short isoform of D2 receptor
. PLoS One
. 2011
Mar
;6
(3
):e18097
.
[PubMed]
1932-620330.
Castillo
LF
, Rivero
EM
, Goffin
V
, Lüthy
IA
. Alpha2-adrenoceptor agonists trigger prolactin signaling in breast cancer cells
. Cell Signal
. 2017
Jun
;34
:76
–85
.
[PubMed]
0898-656831.
Dueñas
Z
, Torner
L
, Corbacho
AM
, Ochoa
A
, Gutiérrez-Ospina
G
, López-Barrera
F
, et al.. Inhibition of rat corneal angiogenesis by 16-kDa prolactin and by endogenous prolactin-like molecules
. Invest Ophthalmol Vis Sci
. 1999
Oct
;40
(11
):2498
–505
.
[PubMed]
0146-040432.
Ochoa
A
, Montes de Oca
P
, Rivera
JC
, Dueñas
Z
, Nava
G
, de La Escalera
GM
, et al.. Expression of prolactin gene and secretion of prolactin by rat retinal capillary endothelial cells
. Invest Ophthalmol Vis Sci
. 2001
Jun
;42
(7
):1639
–45
.
[PubMed]
0146-040433.
Ferraris
J
, Bernichtein
S
, Pisera
D
, Goffin
V
. Use of prolactin receptor antagonist to better understand prolactin regulation of pituitary homeostasis
. Neuroendocrinology
. 2013
;98
(3
):171
–9
.
[PubMed]
0028-383534.
Gu
L
, Liao
Z
, Hoang
DT
, Dagvadorj
A
, Gupta
S
, Blackmon
S
, Ellsworth
E
, Talati
P
, Leiby
B
, Zinda
M
, Lallas
CD
, Trabulsi
EJ
, McCue
P
, Gomella
L
, Huszar
D
, Nevalainen
MT
: Pharmacologic inhibition of jak2-stat5 signaling by jak2 inhibitor azd1480 potently suppresses growth of both primary and castrate-resistant prostate cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research 2013
;19:5658-5674.35.
Ferbeyre
G
, Moriggl
R
. The role of Stat5 transcription factors as tumor suppressors or oncogenes
. Biochim Biophys Acta
. 2011
Jan
;1815
(1
):104
–14
.
[PubMed]
0006-300236.
Berchtold
S
, Moriggl
R
, Gouilleux
F
, Silvennoinen
O
, Beisenherz
C
, Pfitzner
E
, et al.. Cytokine receptor-independent, constitutively active variants of STAT5
. J Biol Chem
. 1997
Nov
;272
(48
):30237
–43
.
[PubMed]
0021-925837.
Creamer
BA
, Sakamoto
K
, Schmidt
JW
, Triplett
AA
, Moriggl
R
, Wagner
KU
. Stat5 promotes survival of mammary epithelial cells through transcriptional activation of a distinct promoter in Akt1
. Mol Cell Biol
. 2010
Jun
;30
(12
):2957
–70
.
[PubMed]
0270-730638.
Gilbert
S
, Nivarthi
H
, Mayhew
CN
, Lo
YH
, Noah
TK
, Vallance
J
, et al.. Activated STAT5 confers resistance to intestinal injury by increasing intestinal stem cell proliferation and regeneration
. Stem Cell Reports
. 2015
Feb
;4
(2
):209
–25
.
[PubMed]
2213-671139.
Booth
A
, Trudeau
T
, Gomez
C
, Lucia
MS
, Gutierrez-Hartmann
A
. Persistent ERK/MAPK activation promotes lactotrope differentiation and diminishes tumorigenic phenotype
. Mol Endocrinol
. 2014
Dec
;28
(12
):1999
–2011
.
[PubMed]
0888-880940.
Sirzen-Zelenskaya
A
, Gonzalez-Iglesias
AE
, Boutet de Monvel
J
, Bertram
R
, Freeman
ME
, Gerber
U
, et al.. Prolactin induces a hyperpolarising current in rat paraventricular oxytocinergic neurones
. J Neuroendocrinol
. 2011
Oct
;23
(10
):883
–93
.
[PubMed]
0953-819441.
Mäkelä
J
, Koivuniemi
R
, Korhonen
L
, Lindholm
D
. Interferon-gamma produced by microglia and the neuropeptide PACAP have opposite effects on the viability of neural progenitor cells
. PLoS One
. 2010
Jun
;5
(6
):e11091
.
[PubMed]
1932-620342.
Waters
MJ
, Brooks
AJ
. JAK2 activation by growth hormone and other cytokines
. Biochem J
. 2015
Feb
;466
(1
):1
–11
.
[PubMed]
0264-602143.
Haedo
MR
, Gerez
J
, Fuertes
M
, Giacomini
D
, Páez-Pereda
M
, Labeur
M
, et al.. Regulation of pituitary function by cytokines
. Horm Res
. 2009
;72
(5
):266
–74
.
[PubMed]
0301-016344.
Li
G
, Miskimen
KL
, Wang
Z
, Xie
XY
, Tse
W
, Gouilleux
F
, et al.. Effective targeting of STAT5-mediated survival in myeloproliferative neoplasms using ABT-737 combined with rapamycin
. Leukemia
. 2010
Aug
;24
(8
):1397
–405
.
[PubMed]
0887-692445.
Kieslinger
M
, Woldman
I
, Moriggl
R
, Hofmann
J
, Marine
JC
, Ihle
JN
, et al.. Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation
. Genes Dev
. 2000
Jan
;14
(2
):232
–44
.
[PubMed]
0890-936946.
Mirtti
T
, Leiby
BE
, Abdulghani
J
, Aaltonen
E
, Pavela
M
, Mamtani
A
, et al.. Nuclear Stat5a/b predicts early recurrence and prostate cancer-specific death in patients treated by radical prostatectomy
. Hum Pathol
. 2013
Mar
;44
(3
):310
–9
.
[PubMed]
0046-817747.
Sackmann-Sala
L
, Chiche
A
, Mosquera-Garrote
N
, Boutillon
F
, Cordier
C
, Pourmir
I
, et al.. Prolactin-induced prostate tumorigenesis links sustained Stat5 signaling with the amplification of basal/stem cells and emergence of putative luminal progenitors
. Am J Pathol
. 2014
Nov
;184
(11
):3105
–19
.
[PubMed]
0002-944048.
Auernhammer
CJ
, Dorn
F
, Vlotides
G
, Hengge
S
, Kopp
FB
, Spoettl
G
, et al.. The oncostatin M receptor/gp130 ligand murine oncostatin M induces apoptosis in adrenocortical Y-1 tumor cells
. J Endocrinol
. 2004
Mar
;180
(3
):479
–86
.
[PubMed]
0022-079549.
Zaldivar
V
, Magri
ML
, Zárate
S
, Jaita
G
, Eijo
G
, Radl
D
, et al.. Estradiol increases the Bax/Bcl-2 ratio and induces apoptosis in the anterior pituitary gland
. Neuroendocrinology
. 2009
;90
(3
):292
–300
.
[PubMed]
0028-383550.
Eijo
G
, Zárate
S
, Jaita
G
, Ferraris
J
, Magri
ML
, Zaldivar
V
, et al.. Inhibition of nuclear factor-kappa B sensitises anterior pituitary cells to tumour necrosis factor-α- and lipopolysaccharide-induced apoptosis
. J Neuroendocrinol
. 2011
Aug
;23
(8
):651
–9
.
[PubMed]
0953-819451.
Booth
AK
, Gutierrez-Hartmann
A
. Signaling pathways regulating pituitary lactotrope homeostasis and tumorigenesis
. Adv Exp Med Biol
. 2015
;846
:37
–59
.
[PubMed]
0065-259852.
Roof
AK
, Jirawatnotai
S
, Trudeau
T
, Kuzyk
C
, Wierman
ME
, Kiyokawa
H
, et al.. The balance of pi3k and erk signaling is dysregulated in prolactinoma and modulated by dopamine
. Endocrinology
. 2018
Jun
;159
(6
):2421
–34
.
[PubMed]
0013-722753.
Newey
PJ
, Gorvin
CM
, Cleland
SJ
, Willberg
CB
, Bridge
M
, Azharuddin
M
, et al.. Mutant prolactin receptor and familial hyperprolactinemia
. N Engl J Med
. 2013
Nov
;369
(21
):2012
–20
.
[PubMed]
0028-479354.
Bernard
V
, Villa
C
, Auguste
A
, Lamothe
S
, Guillou
A
, Martin
A
, et al.. Natural and molecular history of prolactinoma: insights from a Prlr-/- mouse model
. Oncotarget
. 2017
Dec
;9
(5
):6144
–55
.
[PubMed]
1949-255355.
Ferraris
J
, Radl
DB
, Zárate
S
, Jaita
G
, Eijo
G
, Zaldivar
V
, et al.. N-terminal prolactin-derived fragments, vasoinhibins, are proapoptoptic and antiproliferative in the anterior pituitary
. PLoS One
. 2011
;6
(7
):e21806
.
[PubMed]
1932-620356.
Bernard
V
, Lamothe
S
, Beau
I
, Guillou
A
, Martin
A
, Le Tissier
P
, et al.. Autocrine actions of prolactin contribute to the regulation of lactotroph function in vivo
. FASEB J
. 2018
Sep
;32
(9
):4791
–7
.
[PubMed]
0892-663857.
Recouvreux
MV
, Camilletti
MA
, Rifkin
DB
, Díaz-Torga
G
. The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas
. J Endocrinol
. 2016
Mar
;228
(3
):R73
–83
.
[PubMed]
0022-0795© 2018 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2018
You do not currently have access to this content.
