Stimulation of prolactin receptor induces STAT-5 phosphorylation and cellular invasion in glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans and is characterized with poor outcome. In this study, we investigated components of prolactin (Prl) system in cell models of GBM and in histological tissue sections obtained from GBM patients. Expression of Prolactin receptor (PrlR) was detected at high levels in U251-MG, at low levels in U87-MG and barely detectable in U373 cell lines and in 66% of brain tumor tissues from 32 GBM patients by immunohistochemical technique. In addition, stimulation of U251-MG and U87-MG cells but not U373 with Prl resulted in increased STAT5 phosphorylation and only in U251-MG cells with increased cellular invasion. Furthermore, STAT5 phosphorylation and cellular invasion induced in Prl stimulated cells were significantly reduced by using a Prl receptor antagonist that consists of Prl with four amino acid replacements. We conclude that Prl receptor is expressed at different levels in the majority of GBM tumors and that blocking of PrlR in U251-MG cells significantly reduce cellular invasion.

Human Cytomegalovirus Infection Induces High Expression of Prolactin and Prolactin Receptors in Ovarian Cancer

“…A PRLR blocking monoclonal antibody showed significant antitumor activity against MCF7 breast cancer xenografts [59]. Our previous study in glioblastoma demonstrated increased PRLR expression levels and indicated some efficacy to reduce tumor cell growth by using PRLRA in experimental systems [39]. These data support the idea that the PRL system is relevant in tumorigenesis and that agents blocking the receptor or drugs conjugated with PRLRA may be of relevance for future pharmaceutical development [60].…”

“…It stimulates proliferation of different cell types in the body and has been linked to enhanced tumor cell growth [35][36][37]. Increased PRLR levels in tumors may therefore stimulate cancer cell growth via PRL [38,39]. Recent findings demonstrate that PRL production is not only restricted to the pituitary gland [40], which makes this theory interesting.…”

“…In humans, there is a specific gene promoter allowing for PRL production in extra-pituitary locations [41], which implies that PRL not only functions as a regular hormone but potentially also as a local growth factor. Activation of the PRLR by PRL leads to activation of the JAK/STAT pathway [39,42]. Several publications suggest that activation of the PRL/PRLR signaling pathways is linked to cancer via activation of PI3K, AKT, and MAPK pathways, which are important in tumorigenesis [43][44][45].…”

Targeted nanocomplex carrying siRNA against MALAT1 sensitizes glioblastoma to temozolomide

“…The pituitary hormone prolactin (PRL) is another component that significantly reduced by MALAT1 silencing. Interestingly, it was shown that PRL is overexpressed in GBM tumor and increases invasiveness of GBM cells by inducing phosphorylation of STAT5 ( 39 ). Expression of other signaling molecules including IL-8, VEGF-C, HB-EGF and NRG1 were also significantly reduced with MALAT1 silencing.…”

Glioblastoma research: US and international networking achievements

“…A look into the most prestigious scientific journals such as the New England Journal of Medicine [ 3 ], Lancet [ 4 , 5 ] or Journals of the American Medical Association [ 6 ] reveals an impressive number of scientific publications that have been published on this condition to date. A large number of basic and clinical studies have also been published in Oncotarget recently [ 7 – 19 ]. However, patients and their families are traumatized by the diagnosis.…”