Prolactin and its receptor as therapeutic targets in glioblastoma multiforme

Antonela Sofía Asad,Nazareno Gonzalez,Araceli Abt,Adriana Seilicovich,Camila Florencia Zuccato,Daniel Alberto Pisera,Florence Boutillon,Alejandro Javier Nicola Candia,María Jimena Ferraris,Vincent Goffin,Santiago Jordi Orrillo,Marianela Candolfi,Emilio De Simone,Yael Lastra

doi:10.1038/s41598-019-55860-x

Abstract

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.

Highlights

Www.nature.com/scientificreports been reported to promote tumour cell proliferation, angiogenesis[4,5,6] and chemoresistance[7,8]
While PRL was detected in the supernatant of C6 glioblastomas multiforme (GBM) cells (6–22 ng/ml), PRL levels in the supernatant of U251-MG cells were under the detection threshold
Considering that the ability of tumour cells to migrate requires the activation of matrix metalloproteinases (MMP)[19], we evaluated whether the activity of MMPs in GBM cell culture supernatant was stimulated by PRL

Summary

Introduction

Www.nature.com/scientificreports been reported to promote tumour cell proliferation, angiogenesis[4,5,6] and chemoresistance[7,8]. Various isoforms of the PRLR, i.e. long, intermediate and short, result from alternative splicing and vary in the length of the intracellular domain[9] Since they encompass different signalling pathways, the relative expression of these receptors in normal and pathological tissues may explain, in part, the versatility of PRL actions reported in several tissues, such as the healthy and neoplastic mammary gland[3]. In order to shed light on the role of PRL and PRLR in the pathogenesis of GBM, we evaluated proliferation, viability, chemosensitivity and migration of GBM cells in response to PRL stimulation or PRLR signalling blockade using the receptor-specific antagonist ∆1–9-G129R-hPRL (PRLR-A)[17], and to the overexpression of the long and short isoforms of PRLR. Our findings suggest that the activation of the PRL/PRLR pathway may facilitate GBM tumour progression

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