Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells

Int J Mol Sci. 2018 Mar 15;19(3):864. doi: 10.3390/ijms19030864.

Abstract

Glioblastomas (GBM) are the most frequent and aggressive brain tumors. In these malignancies, progesterone (P4) promotes proliferation, migration, and invasion. The P4 metabolite allopregnanolone (3α-THP) similarly promotes cell proliferation in the U87 human GBM cell line. Here, we evaluated global changes in gene expression of U87 cells treated with 3α-THP, P4, and the 5α-reductase inhibitor, finasteride (F). 3α-THP modified the expression of 137 genes, while F changed 90. Besides, both steroids regulated the expression of 69 genes. After performing an over-representation analysis of gene ontology terms, we selected 10 genes whose products are cytoskeleton components, transcription factors, and proteins involved in the maintenance of DNA stability and replication to validate their expression changes by RT-qPCR. 3α-THP up-regulated six genes, two of them were also up-regulated by F. Two genes were up-regulated by P4 alone, however, such an effect was blocked by F when cells were treated with both steroids. The remaining genes were regulated by the combined treatments of 3α-THP + F or P4 + F. An in-silico analysis revealed that promoters of the six up-regulated genes by 3α-THP possess cyclic adenosine monophosphate (cAMP) responsive elements along with CCAAT/Enhancer binding protein alpha (CEBPα) binding sites. These findings suggest that P4 and 3α-THP regulate different sets of genes that participate in the growth of GBMs.

Keywords: allopregnanolone; astrocytomas; finasteride; glioblastomas; progesterone metabolites.

MeSH terms

  • 5-alpha Reductase Inhibitors / pharmacology
  • Cell Line, Tumor
  • Cytoskeleton / genetics
  • Cytoskeleton / metabolism
  • Finasteride / pharmacology
  • Gene Expression Regulation, Neoplastic*
  • Glioblastoma / genetics*
  • Humans
  • Pregnanolone / pharmacology*
  • Promoter Regions, Genetic
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome / drug effects*
  • Up-Regulation

Substances

  • 5-alpha Reductase Inhibitors
  • Transcription Factors
  • Finasteride
  • Pregnanolone