Prolactin receptor signaling: A novel target for cancer treatment - Exploring anti-PRLR signaling strategies

Abstract

Prolactin (PRL) is a peptide hormone mainly secreted from the anterior pituitary gland. PRL is reported to play a role in pregnancy, mammary gland development, immune modulation, reproduction, and differentiation of islet cells. PRL binds to its receptor PRLR, which belongs to a superfamily of the class I cytokine receptor that has no intrinsic kinase activity. In canonical signaling, PRL binding to PRLR induces downstream signaling including JAK-STAT, AKT and MAPK pathways. This leads to increased cell proliferation, stemness, migration, apoptosis inhibition, and resistance to chemotherapy. PRL-signaling is upregulated in numerous hormone-dependent cancers including breast, prostate, ovarian, and endometrial cancer. However, more recently, the pathway has been reported to play a tumor-promoting role in other cancer types such as colon, pancreas, and hepatocellular cancers. Hence, the signaling pathway is an attractive target for drug development with blockade of the receptor being a potential therapeutic approach. Different strategies have been developed to target this receptor including modification of PRL peptides (Del1-9-G129R-hPRL, G129R-Prl), growth hormone receptor/prolactin receptor bispecific antibody antagonist, neutralizing antibody LFA102, an antibody-drug conjugate (ABBV-176) of the humanized antibody h16f (PR-1594804) and pyrrolobenzodiazepine dimer, a bispecific antibody targeting both PRLR and CD3, an in vivo half-life extended fusion protein containing PRLR antagonist PrlRA and albumin binding domain. There have also been attempts to discover and develop small molecular inhibitors targeting PRLR. Recently, using structure-based virtual screening, we identified a few antipsychotic drugs including penfluridol as a molecule that inhibits PRL-signaling to inhibit PDAC tumor progression. In this review, we will summarize the recent advances in the biology of this receptor in cancer and give an account of PRLR antagonist development for the treatment of cancer.

Network pharmacology and molecular docking reveal potential mechanism of esculetin in the treatment of ulcerative colitis

“…[36] PRL binds to its receptor PRLR, which belongs to the class I cytokine receptor family that has no intrinsic kinase activity. [37] PRLR consists of an extracellular domain, a single transmembrane domain, and an intracellular domain. When PRL binds to PRLR, it causes receptor dimerization, resulting in the initiation of several intracellular signal transduction, including canonical Janus kinase 2/signal transducer and activator of transcription (JAK2/STAT) pathway, MAPK pathway, and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway.…”

Role of STAT3 in pancreatic cancer

“…Receptors for growth factors and cytokines play a key role in the phosphorylation of STAT3 through the recruitment and activation of JAK proteins, which then directly activate STAT3 [ 18 ]. The regulation of gene expression by cytokines and growth factors, such as IL-6, IL-10, IL-23, IL-17, fibroblast growth factor 2 (FGF2), and vascular endothelial growth factor (VEGF) implicates STAT3 as a promoter of cell proliferation and inflammation, stemness, metastasis and chemoresistance ( Table 1 ) [ 10 , 19 , 20 ].…”

“…Another method of STAT3 activation relies on the PRL receptor (PRLR) as observed in hormone-dependent cancers, primarily breast cancer, though an observed increase in PRL expression also persists in PDAC [ 10 , 20 , 46 ]. In our previous study, we demonstrated that PRL binds to the extracellular domain of PRLR which promotes an association with JAK2, thus inducing an activation cascade of downstream pathways, such as STAT3 and STAT5 [ 20 ]. This increased cellular proliferation, cell motility and stemness of Panc-1 and MiaPaCa-2 PDAC cell lines through STAT3 mediated upregulation of the oncogene, Myc.…”

Andrological aspects of prolactin secretion disorders

“…Экспериментальные исследования также показали, что сверхэкспрессия ПРЛ в ПЖ мышей приводит к неорганизованному расширению компартмента базальных/стволовых клеток, который содержит клетки, инициирующие развитие опухоли ПЖ, что также позволяет декларировать важную роль локального ПРЛ в инициации и прогрессировании РПЖ [50]. В связи с этим разработан и тестируется целый ряд фармакологических ингибиторов, нацеленных на различные уровни регуляции метаболического пути PRL-R/Jak/STAT5a/b и предназначенных для лечения распространенного РПЖ [51][52][53]. Кроме того, по мнению некоторых исследователей, лечение прогрессирующего андрогеннезависимого РПЖ должно обязательно включать подавление высоких концентраций ПРЛ в плазме крови, что может быть достигнуто с помощью применения агонистов дофаминовых рецепторов, которое, по данным исследователей, привело к снижению сывороточного уровня ПРЛ на 88 % и стабилизации процесса в ПЖ у всех мужчин с РПЖ [54].…”