Allopregnanolone promotes proliferation and differential gene expression in human glioblastoma cells

Abstract

Allopregnanolone (3α-THP) is one of the main reduced progesterone (P₄) metabolites that is recognized as a neuroprotective and myelinating agent. 3α-THP also induces proliferation of different neural cells. It has been shown that P₄ 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 P₄ (10nM). Interestingly, finasteride (F; 100nM), an inhibitor of 5α-reductase (5αR), an enzyme necessary to metabolize P₄ and produce 3α-THP, blocked the increase in the number of U87 cells induced by P₄. 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. P₄ increased TGFβ1 and EGFR expression, and this effect was blocked by F. These data provide evidence that P₄, 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.

Keywords: 5α-Reductase; Allopregnanolone; Allopregnanolone (PubChem CID: 92787); Finasteride (PubChem CID: 57363); Glioblastomas; Human astrocytomas; Mifepristone (PubChem CID: 55245); Progesterone; Progesterone (PubChem CID: 5994); Proliferation.