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1.
Elife ; 102021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34528511

RESUMO

As part of the maternal adaptations to pregnancy, mice show a rapid, profound reduction in voluntary running wheel activity (RWA) as soon as pregnancy is achieved. Here, we evaluate the hypothesis that prolactin, one of the first hormones to change secretion pattern following mating, is involved in driving this suppression of physical activity levels during pregnancy. We show that prolactin can acutely suppress RWA in non-pregnant female mice, and that conditional deletion of prolactin receptors (Prlr) from either most forebrain neurons or from GABA neurons prevented the early pregnancy-induced suppression of RWA. Deletion of Prlr specifically from the medial preoptic area, a brain region associated with multiple homeostatic and behavioral roles including parental behavior, completely abolished the early pregnancy-induced suppression of RWA. As pregnancy progresses, prolactin action continues to contribute to the further suppression of RWA, although it is not the only factor involved. Our data demonstrate a key role for prolactin in suppressing voluntary physical activity during early pregnancy, highlighting a novel biological basis for reduced physical activity in pregnancy.


Assuntos
Condicionamento Físico Animal , Prolactina/fisiologia , Animais , Feminino , Homeostase , Camundongos , Gravidez , Área Pré-Óptica/metabolismo , Prolactina/metabolismo , Prosencéfalo/metabolismo , Receptores da Prolactina/metabolismo
2.
PLoS One ; 16(6): e0252662, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34077462

RESUMO

Breast cancer cells were reported to up-regulate human prolactin receptor (PRLR) to assist their growth through the utilization of prolactin (PRL) as the growth factor, which makes PRLR a potential therapeutic target for breast cancer. On the other hand, advanced cancer cells tend to down-regulate or shed off stress signal proteins to evade immune surveillance and elimination. In this report, we created a fusion protein consisting of the extracellular domain of MHC class I chain-related protein (MICA), a stress signal protein and ligand of the activating receptor NKG2D of natural killer (NK) cells, and G129R, an antagonistic variant of PRL. We hypothesize that the MICA portion of the fusion protein binds to NKG2D to activate NK cells and the G129R portion binds to PRLR on breast cancer cells, so that the activated NK cells will kill the PRLR-positive breast cancer cells. We demonstrated that the MICA-G129R fusion protein not only binds to human natural killer NK-92 cells and PRLR-positive human breast cancer T-47D cells, but also promotes NK cells to release granzyme B and IFN-γ and enhances the cytotoxicity of NK cells specifically on PRLR-positive cells. The fusion protein, therefore, represents a new approach for the development of breast cancer specific immunotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores da Prolactina/metabolismo , Morte Celular/fisiologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Regulação da Expressão Gênica , Humanos , Imunoterapia , Células Matadoras Naturais , Fosforilação , Ligação Proteica , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais
3.
BMC Cancer ; 21(1): 681, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107902

RESUMO

BACKGROUND: Prolactin receptor (PRLR) is an attractive antibody therapeutic target with expression across a broad population of breast cancers. Antibody efficacy, however, may be limited to subtypes with either PRLR overexpression and/or those where estradiol no longer functions as a mitogen and are, therefore, reliant on PRLR signaling for growth. In contrast a potent PRLR antibody-drug conjugate (ADC) may provide improved therapeutic outcomes extending beyond either PRLR overexpressing or estradiol-insensitive breast cancer populations. METHODS: We derived a novel ADC targeting PRLR, ABBV-176, that delivers a pyrrolobenzodiazepine (PBD) dimer cytotoxin, an emerging class of warheads with enhanced potency and broader anticancer activity than the clinically validated auristatin or maytansine derivatives. This agent was tested in vitro and in vivo cell lines and patient derived xenograft models. RESULTS: In both in vitro and in vivo assays, ABBV-176 exhibits potent cytotoxicity against multiple cell line and patient-derived xenograft breast tumor models, including triple negative and low PRLR expressing models insensitive to monomethyl auristatin (MMAE) based PRLR ADCs. ABBV-176, which cross links DNA and causes DNA breaks by virtue of its PBD warhead, also demonstrates enhanced anti-tumor activity in several breast cancer models when combined with a poly-ADP ribose polymerase (PARP) inhibitor, a potentiator of DNA damage. CONCLUSIONS: Collectively the efficacy and safety profile of ABBV-176 suggest it may be an effective therapy across a broad range of breast cancers and other cancer types where PRLR is expressed with the potential to combine with other therapeutics including PARP inhibitors.


Assuntos
Citotoxinas/metabolismo , Imunoconjugados/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Receptores da Prolactina/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Imunoconjugados/farmacologia , Camundongos , Camundongos SCID , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
4.
Sci Rep ; 11(1): 10372, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990661

RESUMO

Pancreatic islets adapt to insulin resistance of pregnancy by up regulating ß-cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr+/-), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling affects ß-cell development, to understand ß-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from ß-cells. Here, we found that ß-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed ß-cell mass and blunted in vivo glucose-stimulated insulin secretion during pregnancy. When we compared gene expression profile of islets from transgenic mice with global (Prlr+/-) versus ß-cell-specific Prlr reduction (ßPrlR+/-), we found 95 differentially expressed gene, most of them down regulated in the Prlr+/- mice in comparison to the ßPrlR+/- mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr+/- mice are more vulnerable to glucolipotoxicity-induced apoptosis than islets from pregnant ßPrlR+/- mice. These observations suggest that down regulation of prolactin action during pregnancy in non-ß-cells secondarily and negatively affect ß-cell gene expression, and increased ß-cell susceptibility to external insults.


Assuntos
Resistência à Insulina/genética , Células Secretoras de Insulina/patologia , Complicações na Gravidez/patologia , Prolactina/metabolismo , Receptores da Prolactina/metabolismo , Animais , Glicemia/análise , Glicemia/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Camundongos Knockout , Gravidez , Complicações na Gravidez/genética , Receptores da Prolactina/genética
5.
Theranostics ; 11(8): 3898-3915, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664869

RESUMO

Prolactin binding to the prolactin receptor exerts pleiotropic biological effects in vertebrates. The prolactin receptor (PRLR) has multiple isoforms due to alternative splicing. The biological roles and related signaling of the long isoform (PRLR-LF) have been fully elucidated. However, little is known about the short isoform (PRLR-SF), particularly in cancer development and metabolic reprogramming, a core hallmark of cancer. Here, we reveal the role and underlying mechanism of PRLR-SF in pancreatic ductal adenocarcinoma (PDAC). Methods: A human PDAC tissue array was used to investigate the clinical relevance of PRLR in PDAC. The in vivo implications of PRLR-SF in PDAC were examined in a subcutaneous xenograft model and an orthotopic xenograft model. Immunohistochemistry was performed on tumor tissue obtained from genetically engineered KPC (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) mice with spontaneous tumors. 13C-labeled metabolite measures, LC-MS, EdU incorporation assays and seahorse analyses were used to identify the effects of PRLR-SF on the pentose phosphate pathway and glycolysis. We identified the molecular mechanisms by immunofluorescence, coimmunoprecipitation, proximity ligation assays, chromatin immunoprecipitation and promoter luciferase activity. Public databases (TCGA, GEO and GTEx) were used to analyze the expression and survival correlations of the related genes. Results: We demonstrated that PRLR-SF is predominantly expressed in spontaneously forming pancreatic tumors of genetically engineered KPC mice and human PDAC cell lines. PRLR-SF inhibits the proliferation of PDAC cells (AsPC-1 and BxPC-3) in vitro and tumor growth in vivo. We showed that PRLR-SF reduces the expression of genes in the pentose phosphate pathway (PPP) and nucleotide biosynthesis by activating Hippo signaling. TEAD1, a downstream transcription factor of Hippo signaling, directly regulates the expression of G6PD and TKT, which are PPP rate-limiting enzymes. Moreover, NEK9 directly interacts with PRLR-SF and is the intermediator between PRLR and the Hippo pathway. The PRLR expression level is negatively correlated with overall survival and TNM stage in PDAC patients. Additionally, pregnancy and lactation increase the ratio of PRLR-SF:PRLR-LF in the pancreas of wild-type mice and subcutaneous PDAC xenograft tumors. Conclusion: Our characterization of the relationship between PRLR-SF signaling, the NEK9-Hippo pathway, PPP and nucleotide synthesis explains a mechanism for the correlation between PRLR-SF and metabolic reprogramming in PDAC progression. Strategies to alter this pathway might be developed for the treatment or prevention of pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Quinases Relacionadas a NIMA/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores da Prolactina/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Glucosefosfato Desidrogenase/genética , Xenoenxertos , Humanos , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Nucleotídeos/biossíntese , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Via de Pentose Fosfato , Medicina de Precisão , Prognóstico , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores da Prolactina/química , Receptores da Prolactina/genética , Transdução de Sinais , Fatores de Transcrição/metabolismo , Transcetolase/genética
6.
Braz J Med Biol Res ; 54(5): e10274, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33729390

RESUMO

Prolactin (PRL) plays critical roles in regulation of biological functions with the binding of specific prolactin receptor (PRLR). Revealing the expression patterns of PRLR at different developmental stages is beneficial to better understand the role of PRL and its mechanism of action in striped hamsters. In this study, the cDNA sequence of PRLR (2866-base-pairs) was harvested from the pituitary of mature female striped hamsters (Cricetulus barabensis) that contains an 834-base-pair 5'-untranslated region (1-834 bp), a 1848-base-pair open reading frame (835-2682 bp), and a 184-base-pair 3'-untranslated region (2683-2866). The 1848-base-pair open reading frame encodes a mature prolactin-binding protein of 592 amino acids. In the mature PRLR, two prolactin-binding motifs, 12 cysteines, and five potential Asn-linked glycosylation sites were detected. Our results showed that the PRLR mRNA quantity in the hypothalamus, pituitary, ovaries, or testis was developmental-stage-dependent, with the highest level at sub-adult stage and the lowest level at old stage. We also found that PRLR mRNAs were highest in pituitary, medium level in hypothalamus, and lowest in ovaries or testis. PRLR mRNAs were significantly higher in males than in females, except in the hypothalamus and pituitary from 7-week-old striped hamsters. Moreover, the PRLR mRNAs in the hypothalamus, pituitary, and ovaries or testis were positively correlated with the expression levels of GnRH in the hypothalamus. These results indicated that the PRLR has conserved domain in striped hamster, but also possesses specific character. PRLR has multiple biological functions including positively regulating reproduction in the striped hamster.


Assuntos
Prolactina , Receptores da Prolactina , Animais , Cricetinae , DNA Complementar/genética , Feminino , Masculino , Hipófise/metabolismo , Prolactina/genética , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Análise de Sequência
7.
Reprod Toxicol ; 101: 63-73, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33675932

RESUMO

We have reported sub-fertility in F1 progeny rats with gestational exposure to hexavalent chromium [Cr(VI)], which had disrupted Sertoli cell (SC) structure and function, and decreased testosterone (T). However, the underlying mechanism for reduced T remains to be understood. We tested the hypothesis "transient prenatal exposure to Cr(VI) affects testicular steroidogenesis by altering hormone receptors and steroidogenic enzyme proteins in Leydig cells (LCs)." Pregnant Wistar rats were given drinking water containing 50, 100, and 200 mg/L potassium dichromate during gestational days 9-14, encompassing fetal differentiation window of the testis from the bipotential gonad. F1 male rats were euthanized on postnatal day 60 (peripubertal rats with adult-type LCs alone). Results showed that prenatal exposure to Cr(VI): (i) increased accumulation of Cr(III) in the testis of F1 rats; (ii) increased serum levels of luteinizing and follicle stimulating hormones (LH and FSH), and 17ß estradiol, and decreased prolactin and T; (iii) decreased steroidogenic acute regulatory protein, cytochrome P450 11A1, cytochrome P450 17A1, 3ß- and 17ß-hydroxysteroid dehydrogenases, cytochrome P450 aromatase and 5α reductase proteins, (iv) decreased specific activities of 3ß and 17ß hydroxysteroid dehydrogenases; (v) decreased receptors of LH, androgen and estrogen in LCs; (vi) decreased 5α reductase and receptor proteins of FSH, androgen, and estrogen in SCs. The current study concludes that prenatal exposure to Cr(VI) disrupts testicular steroidogenesis in F1 progeny by repressing hormone receptors and key proteins of the steroidogenic pathway in LCs and SCs.


Assuntos
Carcinógenos Ambientais/toxicidade , Cromo/toxicidade , Dicromato de Potássio/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Testículo/efeitos dos fármacos , 17-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Colestenona 5 alfa-Redutase/metabolismo , Cromo/sangue , Feminino , Hormônios/sangue , Masculino , Troca Materno-Fetal , Dicromato de Potássio/sangue , Gravidez , Ratos Wistar , Receptores do LH/metabolismo , Receptores da Prolactina/metabolismo , Receptores de Esteroides/metabolismo , Testículo/metabolismo , Testículo/patologia
8.
J Immunol Res ; 2021: 6630715, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763492

RESUMO

Systemic lupus erythematosus is characterized by high levels of IgG class autoantibodies that contribute to the pathophysiology of the disease. The formation of these autoantibodies occurs in the germinal centers, where there is cooperation between follicular T helper cells (TFH) and autoreactive B cells. Prolactin has been reported to exacerbate the clinical manifestations of lupus by increasing autoantibody concentrations. The objective of this study was to characterize the participation of prolactin in the differentiation and activation of TFH cells, by performing in vivo and in vitro tests with lupus-prone mice, using flow cytometry and real-time PCR. We found that TFH cells express the long isoform of the prolactin receptor and promoted STAT3 phosphorylation. Receptor expression was higher in MRL/lpr mice and correlative with the manifestations of the disease. Although prolactin does not intervene in the differentiation of TFH cells, it does favor their activation by increasing the percentage of TFH OX40+ and TFH IL21+ cells, as well as leading to high serum concentrations of IL21. These results support a mechanism in which prolactin participates in the emergence of lupus by inducing overactive TFH cells and perhaps promoting dysfunctional germinal centers.


Assuntos
Centro Germinativo/imunologia , Interleucinas/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Prolactina/metabolismo , Receptores OX40/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoanticorpos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos MRL lpr , Receptores OX40/genética , Receptores da Prolactina/metabolismo , Fator de Transcrição STAT3/metabolismo , Regulação para Cima
9.
Reprod Biomed Online ; 42(4): 699-707, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33608185

RESUMO

RESEARCH QUESTION: What is the gene expression pattern of prolactin receptor (PRLR) in human pre-implantation embryos and what are its functions during the embryonic development and adhesion process? DESIGN: A total of 405 discarded human vitrified oocytes and embryos donated for research by consenting couples were used in this study. The oocytes and embryos were used to analyse PRLR expression and to evaluate the influence of prolactin (PRL) supplementation in the embryo culture medium on embryo developmental competence and viability. The rates of blastocyst development and adhesion, outgrowth area, cytoskeletal reorganization and nascent adhesion formation were compared between groups. RESULTS: PRLR expression increased significantly after embryo compaction (P < 0.0001) and blastulation (P < 0.0001). Supplementation of the embryo culture medium with PRL did not improve the developmental rate and morphological grade. In contrast, blastocyst outgrowth was significantly increased in embryos cultured with PRL (P = 0.0004). Phosphorylation of JAK2, downstream of the prolactin receptor family, was markedly higher in the PRL-treated embryos than in embryos cultured without PRL. Furthermore, the expression of mRNAs encoding ezrin-radixin-moesin proteins and epithelial-mesenchymal transition-related genes was stimulated by the activation of PRL-JAK2 signalling. The PRL-treated embryos had higher mRNA expression of integrins than non-treated embryos, and transcriptional repression of cadherin 1 was observed after PRL treatment. More nascent adherent cells expressed focal adhesion kinase and paxillin in PRL-treated embryos than in non-treated embryos. CONCLUSIONS: Human embryos express PRLR at the morula and blastocyst stages, and PRLR signalling stimulates blastocyst adhesion by promoting integrin-based focal adhesions and cytoskeletal organization during trophoblast outgrowth.


Assuntos
Embrião de Mamíferos/metabolismo , Oócitos/metabolismo , Prolactina/metabolismo , Receptores da Prolactina/metabolismo , Adesões Focais , Humanos
10.
Mol Neurobiol ; 58(4): 1846-1858, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33409838

RESUMO

Among the more than 300 functions attributed to prolactin (PRL), this hormone has been associated with the induction of neurogenesis and differentiation of olfactory neurons especially during pregnancy, which are essential for maternal behavior. Despite the original hypothesis that PRL enters the central nervous system through a process mediated by PRL receptors (PRLR) at the choroid plexus (CP), recent data suggested that PRL transport into the brain is independent of its receptors. Based on transcriptomic data suggesting that PRL could be expressed in the CP, this work aimed to confirm PRL synthesis and secretion by CP epithelial cells (CPEC). The secretion of PRL and the distribution of PRLR in CPEC were further characterized using an in vitro model of the rat blood-cerebrospinal fluid barrier. RT-PCR analysis of PRL transcripts showed its presence in pregnant rat CP, in CPEC, and in the rat immortalized CP cell line, Z310. These observations were reinforced by immunocytochemistry staining of PRL in CPEC and Z310 cell cytoplasm. A 63-kDa immunoreactive PRL protein was detected by Western blot in CP protein extracts as well as in culture medium incubated with rat pituitary and samples of rat cerebrospinal fluid and serum. Positive immunocytochemistry staining of PRLR was present throughout the CPEC cytoplasm and in the apical and basal membrane of these cells. Altogether, our evidences suggest that CP is an alternative source of PRL to the brain, which might impact neurogenesis of olfactory neurons at the subventricular zone, given its proximity to the CP.


Assuntos
Plexo Corióideo/metabolismo , Prolactina/metabolismo , Animais , Plexo Corióideo/citologia , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Modelos Biológicos , Peptídeos/metabolismo , Gravidez , Prolactina/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Receptores da Prolactina/metabolismo
11.
Acta Histochem ; 123(1): 151657, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33259941

RESUMO

Prolactin receptor (PRLR), a type-1 cytokine receptor, is overexpressed in a number of cancer types. It has attracted much attention for putative pro-oncogenic roles, which however, remains controversial in some malignancies. In this study, we reported the localization of PRLR to the Hodgkin's and Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL), a neoplasm of predominantly B cell origin. Immunohistochemistry performed on 5-µm thick FFPE sections revealed expression of PRLR in HRS cells. Cellular immunofluorescence experiments showed that the HL-derived cell lines, Hs445, KMH2 and L428 overexpressed PRLR. The PRLR immunofluorescent signal was depleted after treating the cell lines with 10 µM of siRNA for 48 h. We also tested whether PRLR is involved in the growth of HL, in vitro. One-way analysis of variance (ANOVA) on cell growth data obtain from WST-1 cell proliferation assay and trypan blue exclusion assay and hemocytometry showed that siRNA-depletion of PRLR expression resulted in decreased growth in all three cell lines. These results offered only a short insight into the involvement of PRLR in HL. As a result, further investigation is required to decipher the precise role(s) of PRLR in the pathogenesis of HL.


Assuntos
Doença de Hodgkin/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores da Prolactina/metabolismo , Células de Reed-Sternberg/metabolismo , Linhagem Celular Tumoral , Doença de Hodgkin/patologia , Humanos , Imuno-Histoquímica , Células de Reed-Sternberg/patologia
12.
Gen Comp Endocrinol ; 301: 113657, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33159912

RESUMO

The hormone prolactin has many diverse functions across taxa such as osmoregulation, metabolism, and reproductive behavior. In ring doves, central prolactin action is important for parental care and feeding behavior. However, there is a considerable lack of information on the distribution of the prolactin receptor (PRLR) in the avian CNS to test the hypothesis that prolactin mediates these and other functions in other birds. In order to advance this research, we collected brains from breeding and non-breeding zebra finches to map the PRLR distribution using immunohistochemistry. We found PRLRs are distributed widely across the brain, both in hypothalamic sites known to regulate parental care and feeding, but also in many non-hypothalamic sites, including the tectofugal visual pathway, song system regions, reward associated areas, and pallium. This raises the possibility that prolactin has other functions throughout the brain that are not necessarily related to feeding or parental care. In addition, we also stained brains for pSTAT5, a transcription factor which is expressed when the PRLR is activated and is used as a marker for PRLR activity. We found several notable differences in pSTAT5 activity due to the breeding state of the animal, in both directions, further supporting the hypothesis that prolactin has many diverse functions in the brain both within and outside times of breeding. Together, this study represents the first essential step to inform the design of causative studies which manipulate PRLR-expressing cells to test their role in a wide variety of behaviors and other physiological functions.


Assuntos
Tentilhões , Regulação da Expressão Gênica , Receptores da Prolactina , Animais , Cruzamento , Tentilhões/metabolismo , Prolactina , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Reprodução
13.
Braz. j. med. biol. res ; 54(5): e10274, 2021. graf
Artigo em Inglês | LILACS | ID: biblio-1153553

RESUMO

Prolactin (PRL) plays critical roles in regulation of biological functions with the binding of specific prolactin receptor (PRLR). Revealing the expression patterns of PRLR at different developmental stages is beneficial to better understand the role of PRL and its mechanism of action in striped hamsters. In this study, the cDNA sequence of PRLR (2866-base-pairs) was harvested from the pituitary of mature female striped hamsters (Cricetulus barabensis) that contains an 834-base-pair 5′-untranslated region (1-834 bp), a 1848-base-pair open reading frame (835-2682 bp), and a 184-base-pair 3′-untranslated region (2683-2866). The 1848-base-pair open reading frame encodes a mature prolactin-binding protein of 592 amino acids. In the mature PRLR, two prolactin-binding motifs, 12 cysteines, and five potential Asn-linked glycosylation sites were detected. Our results showed that the PRLR mRNA quantity in the hypothalamus, pituitary, ovaries, or testis was developmental-stage-dependent, with the highest level at sub-adult stage and the lowest level at old stage. We also found that PRLR mRNAs were highest in pituitary, medium level in hypothalamus, and lowest in ovaries or testis. PRLR mRNAs were significantly higher in males than in females, except in the hypothalamus and pituitary from 7-week-old striped hamsters. Moreover, the PRLR mRNAs in the hypothalamus, pituitary, and ovaries or testis were positively correlated with the expression levels of GnRH in the hypothalamus. These results indicated that the PRLR has conserved domain in striped hamster, but also possesses specific character. PRLR has multiple biological functions including positively regulating reproduction in the striped hamster.


Assuntos
Animais , Masculino , Feminino , Prolactina/genética , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Hipófise/metabolismo , Cricetinae , Análise de Sequência , DNA Complementar/genética
14.
Aging (Albany NY) ; 12(24): 25939-25955, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33378745

RESUMO

Adult hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow (BM) ensuring homeostasis of blood production and immune response throughout life. Sex differences in immunocompetence and mortality are well-documented in humans. However, whether HSPCs behave dimorphically between sexes during aging remains unknown. Here, we show that a significant expansion of BM-derived HSPCs occurs in the middle age of female but in the old age of male mice. We then show that a decline of HSPCs in male mice, as indicated by the expression levels of select hematopoietic genes, occurs much earlier in the aging process than that in female mice. Sex-mismatched heterochronic BM transplantations indicate that the middle-aged female BM microenvironment plays a pivotal role in sustaining hematopoietic gene expression during aging. Furthermore, a higher concentration of the pituitary sex hormone follicle-stimulating hormone (FSH) in the serum and a concomitant higher expression of its receptor on HSPCs in the middle-aged and old female mice than age-matched male mice, suggests that FSH may contribute to the sexual dimorphism in aging hematopoiesis. Our study reveals that HSPCs in the BM niches are possibly regulated in a sex-specific manner and influenced differently by sex hormones during aging hematopoiesis.


Assuntos
Envelhecimento/fisiologia , Hormônio Foliculoestimulante/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Receptores do FSH/metabolismo , Caracteres Sexuais , Animais , Antígenos Ly/metabolismo , Medula Óssea , Transplante de Medula Óssea , Linhagem da Célula , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Hormônio Foliculoestimulante/metabolismo , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Hematopoese/fisiologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores do LH/genética , Receptores do LH/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Nicho de Células-Tronco
15.
Aging (Albany NY) ; 12(24): 24671-24692, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33335078

RESUMO

Progesterone receptor (PR) isoforms can drive unique phenotypes in luminal breast cancer (BC). Here, we hypothesized that PR-B and PR-A isoforms differentially modify the cross-talk between prolactin and fatty acid synthase (FASN) in BC. We profiled the responsiveness of the FASN gene promoter to prolactin in T47Dco BC cells constitutively expressing PR-A and PR-B, in the PR-null variant T47D-Y cell line, and in PR-null T47D-Y cells engineered to stably re-express PR-A (T47D-YA) or PR-B (T47D-YB). The capacity of prolactin to up-regulate FASN gene promoter activity in T47Dco cells was lost in T47D-Y and TD47-YA cells. Constitutively up-regulated FASN gene expression in T47-YB cells and its further stimulation by prolactin were both suppressed by the prolactin receptor antagonist hPRL-G129R. The ability of the FASN inhibitor C75 to decrease prolactin secretion was more conspicuous in T47-YB cells. In T47D-Y cells, which secreted notably less prolactin and downregulated prolactin receptor expression relative to T47Dco cells, FASN blockade resulted in an augmented secretion of prolactin and up-regulation of prolactin receptor expression. Our data reveal unforeseen PR-B isoform-specific regulatory actions in the cross-talk between prolactin and FASN signaling in BC. These findings might provide new PR-B/FASN-centered predictive and therapeutic modalities in luminal intrinsic BC subtypes.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Ácido Graxo Sintase Tipo I/genética , Prolactina/metabolismo , Receptores de Progesterona/metabolismo , Receptores da Prolactina/genética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Linhagem Celular Tumoral , Bases de Dados Genéticas , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Graxo Sintase Tipo I/metabolismo , Humanos , Interleucina-6/metabolismo , Prolactina/farmacologia , Regiões Promotoras Genéticas , Isoformas de Proteínas , RNA Mensageiro/metabolismo , Receptor Cross-Talk , Receptores de Progesterona/genética , Receptores da Prolactina/antagonistas & inibidores , Receptores da Prolactina/metabolismo , Regulação para Cima
16.
Int J Med Sci ; 17(18): 3174-3189, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173437

RESUMO

Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Receptor alfa de Estrogênio/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Hipofisárias/terapia , Prolactinoma/terapia , Receptores da Prolactina/metabolismo , Adolescente , Adulto , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bromocriptina/farmacologia , Bromocriptina/uso terapêutico , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estradiol/metabolismo , Receptor alfa de Estrogênio/análise , Receptor alfa de Estrogênio/antagonistas & inibidores , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Hipofisectomia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Hipófise/patologia , Hipófise/cirurgia , Neoplasias Hipofisárias/patologia , Prolactina/metabolismo , Prolactinoma/patologia , Ratos , Receptores da Prolactina/análise , Adulto Jovem
17.
Expert Opin Ther Targets ; 24(11): 1121-1133, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32896197

RESUMO

Introduction: Prolactin (PRL) and its receptor (PRLR) have been associated with the development of hormone-dependent tumors and have been detected in glioblastoma (GBM) biopsies. GBM is the most common and aggressive primary brain tumor in adults and the prognosis for patients is dismal; hence researchers are exploring the PRLR pathway as a therapeutic target in this disease. Areas covered: This paper explores the effects of PRLR activation on the biology of GBM, the correlation between PRL and PRLR expression and GBM progression and survival in male and female patients. Finally, we discuss how a better understanding of the PRLR pathway may allow the development of novel treatments for GBM. Expert opinion: We propose PRL and PRLR as potential prognosis biomarkers and therapeutic targets in GBM. Local administration of PRLR inhibitors using gene therapy may offer a beneficial strategy for targeting GBM cells disseminated in the non-neoplastic brain; however, efficacy and safety require careful and extensive evaluation. The data depicted herein underline the need to (i) improve our understanding of sexual dimorphism in GBM, and (ii) develop accurate preclinical models that take into consideration different hormonal contexts, specific genetic alterations, and tumor grades.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Receptores da Prolactina/metabolismo , Adulto , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Terapia Genética/métodos , Glioblastoma/patologia , Humanos , Masculino , Terapia de Alvo Molecular , Prognóstico , Prolactina/metabolismo
18.
Cell ; 182(4): 960-975.e15, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32763155

RESUMO

Parental behavior is pervasive throughout the animal kingdom and essential for species survival. However, the relative contribution of the father to offspring care differs markedly across animals, even between related species. The mechanisms that organize and control paternal behavior remain poorly understood. Using Sprague-Dawley rats and C57BL/6 mice, two species at opposite ends of the paternal spectrum, we identified that distinct electrical oscillation patterns in neuroendocrine dopamine neurons link to a chain of low dopamine release, high circulating prolactin, prolactin receptor-dependent activation of medial preoptic area galanin neurons, and paternal care behavior in male mice. In rats, the same parameters exhibit inverse profiles. Optogenetic manipulation of these rhythms in mice dramatically shifted serum prolactin and paternal behavior, whereas injecting prolactin into non-paternal rat sires triggered expression of parental care. These findings identify a frequency-tuned brain-endocrine-brain circuit that can act as a gain control system determining a species' parental strategy.


Assuntos
Dopamina/metabolismo , Hipotálamo/fisiologia , Neurônios/fisiologia , Comportamento Paterno/fisiologia , Animais , Encéfalo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Optogenética , Técnicas de Patch-Clamp , Prolactina/sangue , Ratos , Ratos Sprague-Dawley , Receptores da Prolactina/deficiência , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo
19.
J Neurosci ; 40(37): 7080-7090, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32801151

RESUMO

Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female, but not male, mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.SIGNIFICANCE STATEMENT Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male, mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.


Assuntos
Hiperalgesia/metabolismo , Neurossecreção , Receptores da Prolactina/metabolismo , Células Receptoras Sensoriais/metabolismo , Caracteres Sexuais , Animais , Dinoprostona/metabolismo , Estrogênios/sangue , Feminino , Humanos , Hiperalgesia/fisiopatologia , Interleucina-6/metabolismo , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Nociceptividade , Receptores da Prolactina/genética , Células Receptoras Sensoriais/fisiologia , Medula Espinal/citologia , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
20.
Gen Comp Endocrinol ; 296: 113518, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32474048

RESUMO

In addition to key mammotrophic hormones such as the pituitary prolactin (PRL) and the ovarian steroids progesterone and estradiol, there are local factors that modulate the tissue dynamics of the mammary glands during pregnancy and lactation. By immunohistochemistry and RT-PCR, we found local transcription and translation of gonadotropin-releasing hormone (GNRH), GNRH receptor (GNRHR), PRL and PRL receptor (PRLR) in mammary glands of adult vizcachas during pregnancy and lactation. Both GNRH and GNRHR showed a lag between protein expression and gene transcription throughout the gestational period: while the highest transcription levels of these genes were recorded at early-pregnancy, the epithelial immunoexpressions of both showed their maximum during lactation. RIA results corroborated the presence of GNRH in mammary glands at all the analyzed stages and confirmed the maximum amount of this peptide in the lactating group. Significant amounts of GNRH were detected in milk samples as well. Conversely, PRL and PRLR shared similar protein and gene expression profiles, all exhibiting maximum values during lactation. GNRH peptide content in mammary glands of females with sulpiride-induced hyperprolactinemia (HP) was significantly lower than that of control females (CT). Although PRL mRNA levels remained unchanged, there was a marked increase in theα-lactalbumin (LALBA) transcription in mammary glands of HP- vs CT-females. These results suggest that after targeting mammary glands, PRL stimulates the expression of milk protein genes, but also, tempers the local expression of GNRH. Mammary gland-explantssupplemented with a GNRH analogue (GN-explants) had no differences in terms of PRLR orLALBA transcription levels compared to CT-explants, so the mammary PRLR signaling would not appear to be modulated by GNRH. Yet, mRNA expression levels of both GNRH and the GNRHR-downstream factor, EGR1, were significantly higher in GN-explants compared to that of CT which would point to a GNRH-positive feedback mechanism. In summary, the local coupled expression of GNRH, GNRHR and EGR1 in the mammary gland throughout pregnancy of vizcachas, the PRL-dependent mammary GNRH secretion as well as the GNRH positive feedback on its own transcription suggest an autocrine-paracrine regulatory mechanism and propose an active role for GNRH in mammary gland tissue remodeling.


Assuntos
Regulação da Expressão Gênica , Hormônio Liberador de Gonadotropina/genética , Homeostase , Glândulas Mamárias Animais/metabolismo , Receptores LHRH/genética , Roedores/genética , Animais , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Epitélio/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Hormônio Liberador de Gonadotropina/metabolismo , Lactação/fisiologia , Ligantes , Especificidade de Órgãos , Gravidez , Prolactina/genética , Prolactina/metabolismo , RNA Mensageiro/metabolismo , Receptores LHRH/metabolismo , Receptores da Prolactina/genética , Receptores da Prolactina/metabolismo , Reprodução , Transdução de Sinais/efeitos dos fármacos
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