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Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells.

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 (3?-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 3?-THP, P4, and the 5?-reductase inhibitor, finasteride (F). 3?-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. 3?-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 3?-THP + F or P4 + F. An in-silico analysis revealed that promoters of the six up-regulated genes by 3?-THP possess cyclic adenosine monophosphate (cAMP) responsive elements along with CCAAT/Enhancer binding protein alpha (CEBP?) binding sites. These findings suggest that P4 and 3?-THP regulate different sets of genes that participate in the growth of GBMs.

SUBMITTER: Zamora-Sanchez CJ

PROVIDER: S-EPMC5877725 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells.

Zamora-Sánchez Carmen J CJ Del Moral-Morales Aylin A Hernández-Vega Ana M AM Hansberg-Pastor Valeria V Salido-Guadarrama Ivan I Rodríguez-Dorantes Mauricio M Camacho-Arroyo Ignacio I

International journal of molecular sciences 20180315 3

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 steroi ...[more]

PMID: 29543748

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Project description:Our previous research demonstrated that the neuroactive progesterone metabolite allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) rapidly induced hippocampal neuron neurite regression (Brinton, 1994). We hypothesized that allopregnanolone-induced neurite regression was a prelude to mitogenesis initiated by a rise in intracellular calcium. Supporting this hypothesis, the current data demonstrate that allopregnanolone, in a dose-dependent manner, induces a significant increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural stem cells (hNSCs) derived from the cerebral cortex. Proliferation was determined by incorporation of bromodeoxyuridine and [3H]thymidine, fluorescence-activated cell sorter analysis of murine leukemia virus-green fluorescent protein-labeled mitotic NPCs, and total cell number counting. Allopregnanolone-induced proliferation was isomer and steroid specific, in that the stereoisomer 3beta-hydroxy-5beta-pregnan-20-one and related steroids did not increase [3H]thymidine uptake. Immunofluorescent analyses for the NPC markers nestin and Tuj1 indicated that newly formed cells were of neuronal lineage. Furthermore, microarray analysis of cell-cycle genes and real-time reverse transcription-PCR and Western blot validation revealed that allopregnanolone increased the expression of genes that promote mitosis and inhibited the expression of genes that repress cell proliferation. Allopregnanolone-induced proliferation was antagonized by the voltage-gated L-type calcium channel (VGLCC) blocker nifedipine, consistent with the finding that allopregnanolone induces a rapid increase in intracellular calcium in hippocampal neurons via a GABA type A receptor-activated VGLCC (Son et al., 2002). These data demonstrate that allopregnanolone significantly increased rat NPC and hNSC proliferation with concomitant regulation in mitotic cell-cycle genes via a VGLCC mechanism. The therapeutic potential of allopregnanolone as a neurogenic molecule is discussed.

Dataset Information

Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells.

Publications

Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells.

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