PRL) And Its Receptor Research Articles

The Human Intermediate Prolactin Receptor I-tail Contributes Breast Oncogenesis by Targeting Ras/MAPK Pathway.

Prolactin and its receptor (PRLr) in humans are significantly involved in breast cancer pathogenesis. The intermediate form of human PRLr (hPRLrI) is produced by alternative splicing and has a novel 13 amino acid tail ("I-tail") gain. hPRLrI induces significant proliferation and anchorage-independent growth of normal mammary epithelia in vitro when coexpressed with the long form hPRLr (hPRLrL). hPRLrL and hPRLrI coexpression is necessary to induce the transformation of mammary epithelia in vivo. The I-tail is associated with the ubiquitin-like protein neural precursor cell expressed developmentally downregulated protein 8. Treatment with the neural precursor cell expressed developmentally downregulated protein 8-activating enzyme inhibitor pevonedistat resulted in increased hPRLrL and the death of breast cancer cells. The goal of this study was to determine the function of the hPRLrI I-tail in hPRLrL/hPRLrI-mediated mammary transformation. hPRLrL/hPRLrI and hPRLrL/hPRLrIΔ13 (I-tail removal mutant) were delivered to MCF10AT cells. Cell proliferation was decreased when hPRLrI I-tail was removed. I-tail deletion decreased anchorage-independent growth and attenuated cell migration. The I-tail was involved in Ras/MAPK signaling but not PI3K/Akt signaling pathway as shown by western blot. I-tail removal resulted in decreased hPRLrI stability. RNA-sequencing data revealed that I-tail removal resulted in differential gene expression induced by prolactin. Ingenuity Pathway Analysis revealed that the activity of ERK was attenuated. Treatment of breast cancer cells with ERK1/2 inhibitor ulixertinib resulted in decreased colony-forming ability and less proliferation. These studies suggest that the hPRLrI I-tail contributed to breast oncogenesis and may be a promising target for the development of new breast cancer therapies.

Codonopsis lanceolata polysaccharide ameliorates high-fat diet induced-postpartum hypogalactia via stimulating prolactin receptor-mediated Jak2/Stat5 signaling

This study aims to investigate the ameliorative effect of Codonopsis lanceolata polysaccharide (PCL) on mice with hypogalatia induced by a high-fat diet (HFD) and the potential underlying mechanism. We found that oral administration of PCL demonstrated significant benefits in countering the negative effects of HFD, including weight gain, hepatic steatosis, mesenteric adipocyte hypertrophy, and abnormal glucose/lipid metabolism. In addition, PCL improved mammary gland development and enhanced lactogenesis performance. Histologically, PCL ameliorated the retardation of ductal growth, reduced mammary fat pad thickness, improved the incomplete linear encapsulation of luminal epithelium and myoepithelium, and increased the proliferation of mammary epithelial cells. Flow cytometry analysis showed that PCL mitigated the detrimental effects of HFD on mammary gland development by promoting the proliferation and differentiation of mammary epithelial cells. Mechanistic studies revealed that PCL upregulated the levels of prolactin (PRL) and its receptor (PRLR) in the mammary gland, activated JAK2/STAT5 signaling pathway, and increased the expression of p63, ERBB4, and NRG1. Overall, PCL can ameliorate HFD-induced hypogalactia by activating PRLR-mediated JAK2/STAT5 signaling. Our findings offer a methodological and theoretical foundation for investigating the functional constituents of traditional Chinese medicine in the treatment of hypogalactia.

Prolactin and the evolution of male pregnancy

Prolactin (PRL) is a multifunctional hormone of broad physiological importance, and is involved in many aspects of fish reproduction, including the regulation of live birth (viviparity) and both male and female parental care. Previous research suggests that PRL also plays an important reproductive role in syngnathid fishes (seahorses, pipefish and seadragons), a group with a highly derived reproductive strategy, male pregnancy - how the PRL axis has come to be co-opted for male pregnancy remains unclear. We investigated the molecular evolution and expression of the genes for prolactin and its receptor (PRLR) in an evolutionarily diverse sampling of syngnathid fishes to explore how the co-option of PRL for male pregnancy has impacted its evolution, and to clarify whether the PRL axis is also involved in regulating reproductive function in species with more rudimentary forms of male pregnancy. In contrast to the majority of teleost fishes, all syngnathid fishes tested carry single copies of PRL and PRLR that cluster genetically within the PRL1 and PRLRa lineages of teleosts, respectively. PRL1 gene expression in seahorses and pipefish is restricted to the pituitary, while PRLRa is expressed in all tissues, including the brood pouch of species with both rudimentary and complex brooding structures. Pituitary PRL1 expression remains stable throughout pregnancy, but PRLRa expression is specifically upregulated in the male brood pouch during pregnancy, consistent with the higher affinity of pouch tissues for PRL hormone during embryonic incubation. Finally, immunohistochemistry of brood pouch tissues reveals that both PRL1 protein and PRLRa and Na+/K+ ATPase-positive cells line the inner pouch epithelium, suggesting that pituitary-derived PRL1 may be involved in brood pouch osmoregulation during pregnancy. Our data provide a unique molecular perspective on the evolution and expression of prolactin and its receptor during male pregnancy, and provide the foundation for further manipulative experiments exploring the role of PRL in this unique form of reproduction.

PRL/PRLR Can Promote Insulin Resistance by Activating the JAK2/STAT5 Signaling Pathway.

Objective Although prolactin (PRL) is known to affect food intake, weight gain, and insulin resistance, its effects on lipid metabolism and underlying mechanisms remain underinvestigated. This study aimed to investigate the effects of PRL and its receptor (PRLR) on fat metabolism in regulating the JAK2/STAT5 signaling pathway. Methods SW872 adipocytes were incubated with oleic acid to establish an insulin resistance (IR) model. Western blot was used to detect the expression of PRLR, JAK2, p-JAK2, STAT5, and p-STAT5. Triglyceride (TG) mass was detected by chemical colorimetry methods. Results Fat droplets in the high-dose and medium-dose PRL groups were significantly higher than in the IR model group. TG mass in the cells was increased significantly compared with the model group. Compared with the control group, the expression of PRLR, p-JAK2, and p-STAT5 were significantly decreased in the IR model group when PRL was intervened for 24 h and 48 h. The expression of PRLR, p-JAK2, and p-STAT5 in the high-dose PRL intervention group increased significantly compared with the model group. The PRLR overexpressing group had significantly increased TG content and PRLR, and JAK2, p-JAK2, STAT5, and p-STAT5 levels compared with the IR model. Conclusion PRL and PRLR are related to fat metabolism, and the PRL/PRLR signaling pathway can promote insulin resistance by activating the JAK2/STAT5 signaling pathway and increasing the deposition of TGs.

The Relevant Participation of Prolactin in the Genesis and Progression of Gynecological Cancers.

Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy, cell growth, and differentiation. However, PRL is nowadays known to have a strong implication in oncogenic processes, making it essential to delve into the mechanisms governing these actions. PRL and its receptor (PRLR) activate a series of effects such as survival, cellular proliferation, migration, invasion, metastasis, and resistance to treatment, being highly relevant in developing certain types of cancer. Because women produce high levels of PRL, its influence in gynecological cancers is herein reviewed. It is interesting that, other than the 23 kDa PRL, whose mechanism of action is endocrine, other variants of PRL have been observed to be produced by tumoral tissue, acting in a paracrine/autocrine manner. Because many components, including PRL, surround the microenvironment, it is interesting to understand the hormone’s modulation in cancer cells. This work aims to review the most important findings regarding the PRL/PRLR axis in cervical, ovarian, and endometrial cancers and its molecular mechanisms to support carcinogenesis.

Polymorphisms of the PRLR Gene and Their Association with Milk Production Traits in Egyptian Buffaloes

Simple SummaryThe two non-synonymous g.11685G>A and g.11773T>C SNPs of PRLR(L2) were significantly associated with milk yield, fat%, and protein%, and mRNA and protein levels of PRL and PRLR in milk somatic cells. GT-animals had the best milk performance; however, AC-animals had inferior milk production. Thus, the selection of buffaloes with GT haplotypes may enhance milk performance in Egyptian buffaloes.Prolactin (PRL) and its receptor (PRLR) were considered as potential genetic markers for milk production and quality traits in cattle. However, little information is available regarding PRLR genetic diversity and association studies with milk traits in Egyptian water buffaloes. Therefore, the present study was conducted to search for mutations in PRLR and determine their associations with milk performance in these animals. Exon3 (E3) and E10 of PRLR were screened for polymorphisms using single strand conformation polymorphism (SSCP) and sequencing in 400 buffaloes. The associations between haplotypes and milk production (fat%, protein%, lactose%, and solid%) traits as well as mRNA and protein levels of PRL and PRLR were studied. Two single nucleotide polymorphisms (SNPs) in E10 were detected: g.11685G>A (p.Ala494Thr) and g.11773T>C (p.Val523Aal). The G and T alleles were wild (ancestral) alleles, while the A and C alleles were mutant alleles. These SNPs resulted in four haplotypes; AC, AT, GC, and GT. Buffaloes with wild GT haplotypes showed significantly higher milk yield, fat% and protein%, mRNA and protein levels of PRL and PRLR in milk somatic cells than other animals. Animals carrying mutant AC haplotype had inferior milk traits and lowest levels of associated mRNAs and proteins. With these results, we could conclude that the selection of buffaloes with wild GT haplotypes for g.11685G>A and g.11773T>C SNPs of the PRLR gene might improve the milk production traits of Egyptian water buffaloes.

Freshening effect on the osmotic response of the Antarctic spiny plunderfish Harpagifer antarcticus.

Global warming is having a significant impact around the world, modifying environmental conditions in many areas, including in zones that have been thermally stable for thousands of years, such as Antarctica. Stenothermal sedentary intertidal fish species may suffer due to warming, notably if this causes water freshening from increased freshwater inputs. Acute decreases in salinity, from 33 down to 5, were used to assess osmotic responses to environmental salinity fluctuations in Antarctic spiny plunderfish Harpagifer antarcticus, in particular to evaluate if H. antarcticus is able to cope with freshening and to describe osmoregulatory responses at different levels (haematological variables, muscle water content, gene expression, NKA activity). H. antarcticus were acclimated to a range of salinities (33 as control, 20, 15, 10 and 5) for 1 week. At 5, plasma osmolality and calcium concentration were both at their lowest, while plasma cortisol and percentage muscle water content were at their highest. At the same salinity, gill and intestine Na+ -K+ -ATPase (NKA) activities were at their lowest and highest, respectively. In kidney, NKA activity was highest at intermediate salinities (15 and 10). The salinity-dependent NKA mRNA expression patterns differed depending on the tissue. Marked changes were also observed in the expression of genes coding membrane proteins associated with ion and water transport, such as NKCC2, CFTR and AQP8, and in the expression of mRNA for the regulatory hormone prolactin (PRL) and its receptor (PRLr). Our results demonstrate that freshening causes osmotic imbalances in H. antarcticus, apparently due to reduced capacity of both transport and regulatory mechanisms of key organs to maintain homeostasis. This has implications for fish species that have evolved in stable environmental conditions in the Antarctic, now threatened by climate change.

Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases

SummaryProlactin (PRL) and its receptor (PRLr) play important roles in the pathogenesis of breast cancer. Cyclophilin A (CypA) is a cis-trans peptidyl-prolyl isomerase (PPI) that is constitutively associated with the PRLr and facilitates the activation of the tyrosine kinase Jak2. Treatment with the non-immunosuppressive prolyl isomerase inhibitor NIM811 or CypA short hairpin RNA inhibited PRL-stimulated signaling, breast cancer cell growth, and migration. Transcriptomic analysis revealed that NIM811 inhibited two-thirds of the top 50 PRL-induced genes and a reduction in gene pathways associated with cancer cell signaling. In vivo treatment of NIM811 in a TNBC xenograft lessened primary tumor growth and induced central tumor necrosis. Deletion of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. The regulation of PRLr/Jak2-mediated biology by NIM811 demonstrates that a non-immunosuppressive prolyl isomerase inhibitor can function as a potential breast cancer therapeutic.

An Overview on the Role of Prolactin and its Receptors in the Reproductive System of Women with External Genital Endometriosis

Numerous studies on animal models endow prolactin with multiple functions, both physiological (reproduction, lactation, growth, metabolism, transport and electrolyte behaviour) and pathological (immunity and carcinogenesis). Prolactin is an acidophilic cells hormone of the anterior pituitary gland. For the past decade, there have been many discoveries regarding the functions of prolactin and its receptor (PRL-R). Prolactin has its effect by binding to membrane-bound receptor isoforms, known as long-form and short-form receptors. The PRL-R receptor is expressed in various tissues, such as the mammary gland, prostate gland, ovaries, immune system cells, adipocytes, liver, etc. One of the most well-known functions of prolactin is to stimulate the proliferation and differentiation of breast cells necessary for lactation. Animal models have provided information on the biology of prolactin proteins and give convincing evidence that each prolactin isoform has independent biological functions. It is important to remember that excessive secretion of this hormone is associated with such symptoms as hypogonadism and infertility. Today, up to 40% of all female infertility cases are caused by hyperproduction of prolactin. One of the infertility causes is a combination of hyperprolactinemia and external genital endometriosis, which is currently not well studied. It remains relevant to determine the role of prolactin and dopamine in the pathogenesis of infertility in women with external genital endometriosis and the possibility of using dopamine agonists in the treatment of this disease. This review focuses on the role of prolactin and its receptors in the pathogenesis of infertility associated with endometriosis.

Cloning and molecular characterization of PRL and PRLR from turbot (Scophthalmus maximus) and their expressions in response to short-term and long-term low salt stress.

The pituitary hormone prolactin (PRL) regulates salt and water homeostasis by altering ion retention and water uptake through peripheral osmoregulatory organs. To understand the role of PRL and its receptor (PRLR) in hypoosmoregulation of turbot (Scophthalmus maximus), we characterized the PRL and PRLR gene and analyzed the tissue distribution of the two genes and their gene transcriptional patterns in the main expressed tissues under long-term and short-term low salt stress. The PRL cDNA is 1486bp in length, incorporating an ORF of 636bp with a putative primary structure of 211 residues. And the PRLR cDNA is 2849bp in length, incorporating an ORF of 1944bp with a putative primary structure of 647 residues. The deduced amino acid sequences of these two genes shared highly conserved structures with those from other teleosts. Quantitative real-time PCR results showed that PRL transcripts were strongly expressed in the pituitary and very weakly in brain, but were hardly expressed in other tissues. PRLR transcripts were most abundant in the kidney, to a lesser extent in the gill, intestine, brain, and spleen, and at low levels in the pituitary and other tissues examined. The expression of PRL in the pituitary increased after short-term or long-term low salt stress, and the highest expression level appeared 12h after stress (P < 0.05). And there is no significant difference between both low salt group (5ppt and 10ppt) at each sampling point. The variation of PRLR expression in gill under short-term low salt stress is similar to that of PRL gene in pituitary, with highest value in 12h (P < 0.05). However, the expression under long-term low salt stress was significantly higher than control group even than 12h group under 5ppt (P < 0.05). The expression of PRLR in the kidney increased first and then decreased after low salt stress, and the highest value also appeared in 12h after stress and there was no significant difference between the salinity groups. After long-term low salt stress, the expression level also increased significantly (P < 0.05), but it was flat with 24h, which was lower than 12h. The variation of PRLR expression in the intestine was basically consistent with that in the kidney. The difference was that the expression level of 24h after stress in the 5ppt group was significantly higher than that of the 10ppt group (P < 0.05). After a comprehensive analysis of the expression levels of the two genes, it can be found that the expression level increased and peaked at 12h after short-term low salt stress, indicating that this time point is the key point for the regulation of turbot in response to low salt stress. This also provides very important information for studying the osmotic regulation of turbot. In addition, our results also showed that the expression of PRLR was stable in the kidney and intestine after long-term low salt stress, while the expression in the gill was much higher than short-term stress. It suggested that PRL and its receptors mainly exert osmotic regulation function in the gill under long-term low salt stress. At the same time, such a result also brings a hint for the low salt selection of turbot, focusing on the regulation of ion transport in the gill.

Prolactin and its receptor as therapeutic targets in glioblastoma multiforme

Although prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to explore their contribution in GBM pathogenesis. We detected PRL and PRLR in all GBM cell lines tested. PRLR activation or overexpression using plasmid transfection increased proliferation, viability, clonogenicity, chemoresistance and matrix metalloproteinase activity in GBM cells, while PRLR antagonist ∆1–9-G129R-hPRL reduced their proliferation, viability, chemoresistance and migration. Meta-analysis of transcriptomic data indicated that PRLR was expressed in all grade II-III glioma (GII-III) and GBM samples. PRL was upregulated in GBM biopsies when compared to GII-III. While in the general population tumour PRL/PRLR expression did not correlate with patient survival, biological sex-stratified analyses revealed that male patients with PRL+/PRLRHIGH GBM performed worse than PRL+/PRLRLOW GBM. In contrast, all male PRL+/PRLRHIGH GII-III patients were alive whereas only 30% of PRL+/PRLRLOW GII-III patients survived after 100 months. Our study suggests that PRLR may be involved in GBM pathogenesis and could constitute a therapeutic target for its treatment. Our findings also support the notion that sexual dimorphism should be taken into account to improve the care of GBM patients.

Interaction between 17\u03b2-estradiol, prolactin and human papillomavirus induce E6/E7 transcript and modulate the expression and localization of hormonal receptors

BackgroundCervical cancer (CC) is the second most common cancer in less developed countries and the second leading cause of death by cancer in women worldwide. The 99% of CC patients are infected with the Human Papilloma Virus (HPV), being HPV16 and HPV18 infection the most frequent. Even though HPV is considered to be a necessary factor for the development of CC, it is not enough, as it requires the participation of other factors such as the hormonal ones. Several studies have demonstrated the requirement of estrogen and its receptors (ERα, ERβ, and GPER) in the precursor lesions progress towards CC. Also, prolactin (PRL) and its receptor (PRLR) have been associated with CC. The molecular mechanisms underlying the cooperation of these hormones with the viral oncoproteins are not well elucidated. For this reason, this study focused on analyzing the contribution of 17β-estradiol (E2), PRL, and HPV on the expression and localization of hormone receptors, as well as to evaluate whether these hormones may promote greater expression of HPV oncogenes and contribute to tumor progression.MethodsqPCR was used to evaluate the effect of E2 and PRL on the expression of E6 and E7 oncoproteins in HeLa and SiHa cervical cancer cells lines. HaCaT cells were transduced with the viral oncogenes E6 and E7 from HPV 16 and 18. ERα, ERβ, GPER, and PRLR expression and localization were evaluated by qPCR, Western blot and immunofluorescence.ResultsE2 and PRL induce E6/E7 oncogenes expression in HeLa and SiHa cells. E6 and E7 oncogenes of HPV16/18 significantly increased the protein expression of ERα, GPER, and PRLR. ERβ was positively regulated only by E6 oncogenes of HPV16/18. Besides, some of these oncogenes modify the location of PRLR toward cytoplasm, and ERα, ERβ, and GPER mainly to the nucleus.ConclusionOur studies suggest that the mutual regulation between E2, PRL, and HPV oncogenes could cooperate with the carcinogenesis process in CC.

Association between prolactin receptor expression and proliferation in the endometrium of obese women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with increased risk of endometrial cancer. There is growing evidence that prolactin and its receptor (PRLR) are involved in the development of cancer. We assessed endometrial expression of PRLR mRNA, and immunostaining of PRLR and the proliferation marker Ki67 on different cycle days in obese (OB-PCOS) and normal-weight women with PCOS and body mass index-matched controls. The OB-PCOS group underwent a 3 months lifestyle intervention. Prior to intervention, obese women with PCOS and controls had lower endometrial levels of PRLR mRNA in proliferative endometrium than the normal-weight groups (p < .05). After intervention, six OB-PCOS women had confirmed ovulation, while 12 remained anovulatory. Both these subgroups displayed higher immunostaining of PRLR in endometrial stroma, and in the anovulatory subgroup also increased Ki67, on cycle days 21–23 compared with controls (p < .05). In obese controls, the PRLR mRNA expression was decreased in secretory endometrium compared with proliferative endometrium (p = .004). A corresponding change within the cycle was not found in OB-PCOS women. Immunostaining of PRLR in the secretory phase correlated positively with Ki67 (p < .05) in the endometrium. These observations suggest that short-term lifestyle intervention can restore ovulation but not normalize PRLR expression in the endometrium of obese women with PCOS. Trial registration: ISRCTN, ISRCTN18400086, https://doi.org/10.1186/ISRCTN18400086

Structural Investigation of Human Prolactin Receptor Transmembrane Domain Homodimerization in a Membrane Environment through Multiscale Simulations.

It is well established that prolactin (PRL) and its receptor (PRLR) are associated with hundreds of biological functions. They have been postulated to be linked to breast and prostate cancers, and PRLR signaling has attracted considerable medical and pharmaceutical interest in the development of compounds targeting PRLR. Dimerization of the receptor through its transmembrane (TM) domain is a key step for understanding its signaling and related issues. Our multiscale simulation results revealed that its TM domain can form dimers in a membrane environment with distinct states stabilized by different residue motifs. On the basis of the simulated data, an activation mechanism of PRL with the importance of two symmetrical tryptophan residues was proposed in detail to determine the conformational change of its receptor, which is essential for signal transduction. The better knowledge of PRLR structure and its protein-protein interaction can considerably contribute to a further understanding of PRLR signaling action and thereby help to develop some new PRLR signaling-based strategies for PRL-related diseases.

Prolactin Signaling Stimulates Invasion via Na(+)/H(+) Exchanger NHE1 in T47D Human Breast Cancer Cells.

Prolactin (PRL) and its receptor (PRLR) are implicated in breast cancer invasiveness, although their exact roles remain controversial. The Na(+)/H(+) exchanger (NHE1) plays essential roles in cancer cell motility and invasiveness, but the PRLR and NHE1 have not previously been linked. Here we show that in T47D human breast cancer cells, which express high levels of PRLR and NHE1, exposure to PRL led to the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5), Akt, and ERK1/2 signaling and the rapid formation of peripheral membrane ruffles, known to be associated with cell motility. NHE1 was present in small ruffles prior to PRL treatment and was further recruited to the larger, more dynamic ruffles induced by PRL exposure. In PRL-induced ruffles, NHE1 colocalized with activated Akt, ERK1/2, and the ERK effector p90Ribosomal S kinase (p90RSK), known regulators of NHE1 activity. Stimulation of T47D cells with PRL augmented p90RSK activation, Ser703-phosphorylation of NHE1, NHE1-dependent intracellular pH recovery, pericellular acidification, and NHE1-dependent invasiveness. NHE1 activity and localization to ruffles were attenuated by the inhibition of Akt and/or ERK1/2. In contrast, noncancerous MCF10A breast epithelial cells expressed NHE1 and PRLR at lower levels than T47D cells, and their stimulation with PRL induced neither NHE1 activation nor NHE1-dependent invasiveness. In conclusion, we show for the first time that PRLR activation stimulates breast cancer cell invasiveness via the activation of NHE1. We propose that PRL-induced NHE1 activation and the resulting NHE1-dependent invasiveness may contribute to the metastatic behavior of human breast cancer cells.

PROLACTIN АND SEROTONIN

An overview of the results of studies on prolactin (PRL) is given. The molecular and genetic characteristics of PRL and its receptor (PRLR) are presented. The PRLR polymorphism in patients with tumors of the breast is described. Synthesized analogues of human PRL inhibited its peripheral effects. The vegetative nervous system modulate PRL secretion. PRL is a risk factor for breast and prostate cancer. The signaling mechanisms of PRL and its possible clinical use in therapy of breast cancer are characterized.

Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle.

Lactation, hair development and homeothermy are characteristic evolutionary features that define mammals from other vertebrate species. Here we describe the discovery of two autosomal dominant mutations with antagonistic, pleiotropic effects on all three of these biological processes, mediated through the prolactin signalling pathway. Most conspicuously, mutations in prolactin (PRL) and its receptor (PRLR) have an impact on thermoregulation and hair morphology phenotypes, giving prominence to this pathway outside of its classical roles in lactation.

Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death

Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism for cell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized G129R, an antagonist peptide of PRL, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced the accumulation of redundant autolysosomes in 3D cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a noncanonical beclin-1-independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival. Our findings provide an understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications.

Пролактин и серотонин

An overview of the results of studies on prolactin (PRL) is given. The molecular and genetic characteristics of PRL and its receptor (PRLR) are presented. The PRLR polymorphism in patients with tumors of the breast is described. Synthesized analogues of human PRL inhibited its peripheral effects. The vegetative nervous system modulate PRL secretion. PRL is a risk factor for breast and prostate cancer. The signaling mechanisms of PRL and its possible clinical use in therapy of breast cancer are characterized.

High expression of prolactin receptor is associated with cell survival in cervical cancer cells

BackgroundThe altered expression of prolactin (PRL) and its receptor (PRLR) has been implicated in breast and other types of cancer. There are few studies that have focused on the analysis of PRL/PRLR in cervical cancer where the development of neoplastic lesions is influenced by the variation of the hormonal status. The aim of this study was to evaluate the expression of PRL/PRLR and the effect of PRL treatment on cell proliferation and apoptosis in cervical cancer cell lines.ResultsHigh expression of multiple PRLR forms and PRLvariants of 60–80 kDa were observed in cervical cancer cell lines compared with non-tumorigenic keratinocytes evaluated by Western blot, immunofluorecence and real time PCR. Treatment with PRL (200 ng/ml) increased cell proliferation in HeLa cells determined by the MTT assay at day 3 and after 1 day a protective effect against etoposide induced apoptosis in HeLa, SiHa and C-33A cervical cancer cell lines analyzed by the TUNEL assay.ConclusionsOur data suggests that PRL/PRLR signaling could act as an important survival factor for cervical cancer. The use of an effective PRL antagonist may provide a better therapeutic intervention in cervical cancer.