Prolactin Induces Apoptosis of Lactotropes in Female Rodents

Abstract

Anterior pituitary cell turnover occurring during female sexual cycle is a poorly understood process that involves complex regulation of cell proliferation and apoptosis by multiple hormones. In rats, the prolactin (PRL) surge that occurs at proestrus coincides with the highest apoptotic rate. Since anterior pituitary cells express the prolactin receptor (PRLR), we aimed to address the actual role of PRL in the regulation of pituitary cell turnover in cycling females. We showed that acute hyperprolactinemia induced in ovariectomized rats using PRL injection or dopamine antagonist treatment rapidly increased apoptosis and decreased proliferation specifically of PRL producing cells (lactotropes), suggesting a direct regulation of these cell responses by PRL. To demonstrate that apoptosis naturally occurring at proestrus was regulated by transient elevation of endogenous PRL levels, we used PRLR-deficient female mice (PRLRKO) in which PRL signaling is totally abolished. According to our hypothesis, no increase in lactotrope apoptotic rate was observed at proestrus, which likely contributes to pituitary tumorigenesis observed in these animals. To decipher the molecular mechanisms underlying PRL effects, we explored the isoform-specific pattern of PRLR expression in cycling wild type females. This analysis revealed dramatic changes of long versus short PRLR ratio during the estrous cycle, which is particularly relevant since these isoforms exhibit distinct signaling properties. This pattern was markedly altered in a model of chronic PRLR signaling blockade involving transgenic mice expressing a pure PRLR antagonist (TGΔ1–9-G129R-hPRL), providing evidence that PRL regulates the expression of its own receptor in an isoform-specific manner. Taken together, these results demonstrate that i) the PRL surge occurring during proestrus is a major proapoptotic signal for lactotropes, and ii) partial or total deficiencies in PRLR signaling in the anterior pituitary may result in pituitary hyperplasia and eventual prolactinoma development, as observed in TGΔ1–9-G129R-hPRL and PRLRKO mice, respectively.

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

“…It has been suggested that PRL inhibits lactotrope functions directly within the pituitary in a dopamine-independent fashion [1]. We have previously shown that PRL increases apoptosis and reduces proliferation of lactotropes [2, 3]. Pharmacologically induced acute hyperprolactinemia also increases apoptosis and decreases proliferation of lactotropes.…”

“…Moreover, the chronic exposure of mice to a pure PRL receptor (PRLR) antagonist (Δ1–9-G129R-hPRL) increases lactotrope proliferation, leading to cell hyperplasia and increased pituitary weight [2]. We also observed that before tumor development, PRLR-deficient mice exhibit alterations in pituitary cell turnover, including decreased apoptotic rate [3]. Taken together, these data indicate that PRL acts as a proapoptotic and antiproliferative factor in lactotropes, which is critical to maintain anterior pituitary cell homeostasis [3].…”

“…We also observed that before tumor development, PRLR-deficient mice exhibit alterations in pituitary cell turnover, including decreased apoptotic rate [3]. Taken together, these data indicate that PRL acts as a proapoptotic and antiproliferative factor in lactotropes, which is critical to maintain anterior pituitary cell homeostasis [3]. These effects contrast with the classical antiapoptotic and/or proliferative effects exerted by PRL in the majority of its target tissues (e.g., mammary gland, prostate, lymphoid cells) [4-14].…”

miR-135a Targets and Regulates Prolactin Receptor Gene in Goat Mammary Epithelial Cells

“…In addition, PRL is associated with immunoregulation, homeostatic maintenance, and tumorigenesis (Bernichtein et al, 2010;Horseman and Gregerson, 2013;Lopez-Pulide et al, 2013). Studies conducted to date have shown that PRL plays central roles in a wide range of biology processes, and all those actions are mediated by the specific cell surface receptor, the prolactin receptor (PRLR), which belongs to the superfamily of hematopoietic cytokine receptors (Ormandy et al, 1997a), combined with PRL activating several signaling pathways, including Janus Kinase-Signal transducer and activator of transcription ( Jak-Stat), mitogen-activated protein kinases (MAPK), and the phosphoinositide 3 kinase (PI3K), and resulting in endpoints such as differentiation, proliferation, survival and secretion (Kelly et al, 2001;Ferraris et al, 2014).…”

Initial study on the possible mechanisms involved in the effects of high doses of perfluorooctane sulfonate (PFOS) on prolactin secretion

“…This hormone has manifold functions: immunological (Freeman et al, 2000), reproductive (Fitzgerald and Dinan, 2008;Egli et al, 2010), growth (Mosa et al, 2015), metabolic (Ben-Jonathan and Hugo, 2015) and behavioral (Babic et al, 2015). Moreover, it can be implicated in breast cancer (Surazynski et al, 2013) and in the regulation of cell proliferation and apoptosis (Ferraris et al, 2014;Hsieh et al, 2014) as well as the prostate gland activity (Rojas-Dur an et al, 2015). Synthesis and secretion of this lactogenic hormone are subjected to multiple regulators.…”