Abstract
Glioblastomas are the most common and aggressive primary brain tumors in adults, and patients with glioblastoma have a median survival of 15 months. Some alternative therapies, such as Src family kinase inhibitors, have failed presumably because other signaling pathways compensate for their effects. In the last ten years, it has been proven that sex hormones such as progesterone (P4) can induce growth, migration, and invasion of glioblastoma cells through its intracellular progesterone receptor (PR), which is mostly known for its role as a transcription factor, but it can also induce non-genomic actions. These non-classic actions are, in part, a consequence of its interaction with cSrc, which plays a significant role in the progression of glioblastomas. We studied the relation between PR and cSrc, and its effects in human glioblastoma cells. Our results showed that P4 and R5020 (specific PR agonist) activated cSrc protein since both progestins increased the p-cSrc (Y416)/cSrc ratio in U251 and U87 human glioblastoma derived cell lines. When siRNA against the PR gene was used, the activation of cSrc by P4 was abolished. The co-immunoprecipitation assay showed that cSrc and PR interact in U251 cells. P4 treatment also promoted the increase in the p-Fak (Y397) (Y576/577)/Fak and the decrease in p-Paxillin (Y118)/Paxillin ratio, which are significant components of the focal adhesion complex and essential for migration and invasion processes. A siRNA against cSrc gene blocked the increase in the p-Fak (Y576/Y577)/Fak ratio and the migration induced by P4, but not the decrease in p-Paxillin (Y118)/Paxillin ratio. We analyzed the potential role of cSrc over PR phosphorylation in three databases, and one putative tyrosine residue in the amino acid 87 of PR was found. Our results showed that P4 induces the activation of cSrc protein through its PR. The latter and cSrc could interact in a bidirectional mode for regulating the activity of proteins involved in migration and invasion of glioblastomas.
Highlights
Astrocytomas are the most common primary brain tumors in the central nervous system (CNS)
We studied the interplay between progesterone receptor (PR) and cSrc, and its effects on the activity of proteins involved in migration and invasion of glioblastoma cells
Activation of cSrc by P4 Is Mediated by PR in Glioblastoma Cells
Summary
Astrocytomas are the most common primary brain tumors in the central nervous system (CNS). Grade IV represents the most malignant astrocytoma, known as glioblastoma [1]. The current standard treatment for glioblastoma has remained unchanged for more than ten years [3]. Some alternatives, such as the use of angiogenesis blockers or Src family kinase inhibitors, have been tested in clinical assays, but none of them with successful outcomes [4, 5] The poor prognosis of patients with glioblastoma is a consequence of the high rate of recurrence of these tumors promoted by the inherently radioresistance and chemo-resistance and the high rate of migration and tumor invasion cells [6]. Glioblastoma cells can spread to the surrounding brain parenchyma, which makes extremely difficult the complete resection of the tumor, and provokes the recurrence of glioblastoma [7]
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