Zamora-Sánchez Carmen J, Hansberg-Pastor Valeria, Salido-Guadarrama Ivan, Rodríguez-Dorantes Mauricio, Camacho-Arroyo Ignacio
Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Mexico.
Facultad de Química, Departamento de Biología, UNAM, Mexico.
Steroids. 2017 Mar;119:36-42. doi: 10.1016/j.steroids.2017.01.004. Epub 2017 Jan 22.
Allopregnanolone (3α-THP) is one of the main reduced progesterone (P) metabolites that is recognized as a neuroprotective and myelinating agent. 3α-THP also induces proliferation of different neural cells. It has been shown that P favors the progression of glioblastomas (GBM), the most common and aggressive primary brain tumors. However, the role of 3α-THP in the growth of GBMs is unknown. Here, we studied the effects of 3α-THP on the number of cells, proliferation and gene expression in U87 cell line derived from a human GBM. 3α-THP (10, 100nM and 1μM) increased the number of U87 cells, and at 10nM exerted a similar increase in both the number of total and proliferative U87 cells as compared with P (10nM). Interestingly, finasteride (F; 100nM), an inhibitor of 5α-reductase (5αR), an enzyme necessary to metabolize P and produce 3α-THP, blocked the increase in the number of U87 cells induced by P. By using RT-qPCR, we determined that U87 cells express 5α-R isoenzymes 1 and 2 (5αR1 and 5αR2), being 5αR1 the predominant one in these cells. 3α-THP (10nM) increased the expression of TGFβ1, EGFR, VEGF and cyclin D1 genes. P increased TGFβ1 and EGFR expression, and this effect was blocked by F. These data provide evidence that P, through its metabolite 3α-THP, can promote in part cell proliferation of human GBM cells by changing the expression of genes involved in tumor progression.
别孕烯醇酮（3α-THP）是主要的还原型孕酮（P）代谢产物之一，被认为是一种神经保护剂和髓鞘形成剂。3α-THP还能诱导不同神经细胞的增殖。研究表明，P有利于胶质母细胞瘤（GBM）的进展，GBM是最常见且侵袭性最强的原发性脑肿瘤。然而，3α-THP在GBM生长中的作用尚不清楚。在此，我们研究了3α-THP对源自人GBM的U87细胞系中细胞数量、增殖和基因表达的影响。3α-THP（10、100 nM和1μM）增加了U87细胞的数量，与P（10 nM）相比，10 nM的3α-THP使U87细胞总数和增殖细胞数量增加程度相似。有趣的是，非那雄胺（F；100 nM），一种5α-还原酶（5αR）的抑制剂，5αR是代谢P并产生3α-THP所必需的酶，它阻断了P诱导的U87细胞数量增加。通过实时定量聚合酶链反应（RT-qPCR），我们确定U87细胞表达5α-R同工酶1和2（5αR1和5αR2），其中5αR1在这些细胞中占主导地位。3α-THP（10 nM）增加了转化生长因子β1（TGFβ1）、表皮生长因子受体（EGFR）、血管内皮生长因子（VEGF）和细胞周期蛋白D1基因的表达。P增加了TGFβ1和EGFR的表达，而这种作用被F阻断。这些数据表明，P通过其代谢产物3α-THP，可通过改变参与肿瘤进展的基因表达，部分促进人GBM细胞的增殖。
