5alpha-dihydroprogesterone promotes proliferation and migration of human glioblastoma cells
STEROIDS
Authors: Zamora-Sanchez, Carmen J.; Hernandez-Vega, Ana M.; Gaona-Dominguez, Saul; Rodriguez-Dorantes, Mauricio; Camacho-Arroyo, Ignacio
Abstract
Glioblastomas (GBMs) are the most common and deadliest intracranial tumors. Steroid hormones, such as progesterone (P4), at physiological concentrations, promote proliferation, and migration of human GBM cells in vivo and in vitro. Neuronal and glial cells, but also GBMs, metabolize P4 and synthesize different active metabolites such as 5 alpha-dihydroprogesterone (5 alpha-DHP). However, their contribution to GBM malignancy remains unknown. Here, we determined the 5 alpha-DHP effects on the number of cells, proliferation, and migration of the U87 and U251 human GBM-derived cell lines. Of the tested concentrations (1 nM-1 mu M), 5 alpha-DHP 10 nM significantly increased the number of U87 and U251 cells from day 2 of treatment, and proliferation (at day 3) in a similar manner as P4 (10 nM). The treatment with the progesterone receptor (PR) antagonist RU486 (mife-pristone), blocked the effects of 5 alpha-DHP on the number of cells and proliferation. Besides, in U251 and LN229 GBM cells, 5 alpha-DHP promoted cell migration (from 12 to 24 h). We also determined that GBM cells expressed the 3 alpha-hydroxysteroid oxidoreductases (3 alpha-HSOR), which reversibly reduce 5 alpha-DHP to allopregnanolone (3 alpha-THP). These data indicate that 5 alpha-DHP induces proliferation and migration of human GBM through the activation of PR.
The role of the prolactin receptor pathway in the pathogenesis of glioblastoma: what do we know so far?
EXPERT OPINION ON THERAPEUTIC TARGETS
Authors: Asad, Antonela S.; Nicola Candia, Alejandro J.; Gonzalez, Nazareno; Zuccato, Camila F.; Seilicovich, Adriana; Candolfi, Marianela
Abstract
Introduction: Prolactin (PRL) and its receptor (PRLR) have been associated with the development of hormone-dependent tumors and have been detected in glioblastoma (GBM) biopsies. GBM is the most common and aggressive primary brain tumor in adults and the prognosis for patients is dismal; hence researchers are exploring the PRLR pathway as a therapeutic target in this disease. Areas covered: This paper explores the effects of PRLR activation on the biology of GBM, the correlation between PRL and PRLR expression and GBM progression and survival in male and female patients. Finally, we discuss how a better understanding of the PRLR pathway may allow the development of novel treatments for GBM. Expert opinion: We propose PRL and PRLR as potential prognosis biomarkers and therapeutic targets in GBM. Local administration of PRLR inhibitors using gene therapy may offer a beneficial strategy for targeting GBM cells disseminated in the non-neoplastic brain; however, efficacy and safety require careful and extensive evaluation. The data depicted herein underline the need to (i) improve our understanding of sexual dimorphism in GBM, and (ii) develop accurate preclinical models that take into consideration different hormonal contexts, specific genetic alterations, and tumor grades.