Intracellular Progesterone Receptor and cSrc Protein Working Together to Regulate the Activity of Proteins Involved in Migration and Invasion of Human Glioblastoma Cells

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.

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The interplay between intracellular progesterone receptor and PKC plays a key role in migration and invasion of human glioblastoma cells

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/j.jsbmb.2016.10.001 ◽

2017 ◽

Vol 172 ◽

pp. 198-206 ◽

Cited By ~ 8

Author(s):

Brenda Marquina-Sánchez ◽

Jesús González-Jorge ◽

Valeria Hansberg-Pastor ◽

Talia Wegman-Ostrosky ◽

Noemi Baranda-Ávila ◽

...

Keyword(s):

Progesterone Receptor ◽

Migration And Invasion ◽

Glioblastoma Cells ◽

Human Glioblastoma ◽

Human Glioblastoma Cells

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Activation of membrane progesterone receptor-alpha increases proliferation, migration, and invasion of human glioblastoma cells

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2018.06.004 ◽

2018 ◽

Vol 477 ◽

pp. 81-89 ◽

Cited By ~ 13

Author(s):

Juan Carlos González-Orozco ◽

Valeria Hansberg-Pastor ◽

Paulina Valadez-Cosmes ◽

Walter Nicolas-Ortega ◽

Yenifer Bastida-Beristain ◽

...

Keyword(s):

Progesterone Receptor ◽

Migration And Invasion ◽

Glioblastoma Cells ◽

Human Glioblastoma ◽

Receptor Alpha ◽

Human Glioblastoma Cells ◽

Membrane Progesterone Receptor ◽

Membrane Progesterone Receptor Alpha

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Interference with PSMB4 Expression Exerts an Anti-Tumor Effect by Decreasing the Invasion and Proliferation of Human Glioblastoma Cells

Cellular Physiology and Biochemistry ◽

10.1159/000487174 ◽

2018 ◽

Vol 45 (2) ◽

pp. 819-831 ◽

Cited By ~ 5

Author(s):

Yu-Chen Cheng ◽

Wen-Chiuan Tsai ◽

Yu-Chi Sung ◽

Hsin-Han Chang ◽

Ying Chen

Keyword(s):

Mouse Model ◽

Migration And Invasion ◽

Glioblastoma Cells ◽

Human Glioblastoma ◽

Xenograft Mouse Model ◽

Study Results ◽

Human Glioblastoma Cells ◽

Brain Tissues

Background/Aims: Glioblastoma (GBM) is a malignant brain tumor with a poor prognosis. Proteasome subunit beta type-4 (PSMB4) is an essential subunit that contributes to the assembly of the 20S proteasome complex. However, the role of PSMB4 in glioblastomas remains to be clarified. The aim of this study was to investigate the role of PSMB4 in GBM tumor progression. Methods: We first analyzed the PSMB4 protein and mRNA expression in 80 clinical brain specimens and 77 datasets from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Next, we inhibited the PSMB4 expression by siRNA in cellular and animal models to explore PSMB4’s underlying mechanisms. The cell survival after siPSMB4 transfection was assayed by MTT assay. Annexin V and propidium iodide staining was used to monitor the apoptosis by flow cytometric analysis. Moreover, the migration and invasion were evaluated by wound healing and Transwell assays. The expression of migration-related and invasion-related proteins after PSMB4 inhibition was detected by Western blotting. In addition, an orthotropic xenograft mouse model was used to assay the effect of PSMB4 knockdown in the in vivo study. Results: Basis on the results of bioinformatics study, glioma patients with higher PSMB4 expression had a shorter survival time than those with lower PSMB4 expression. The staining of clinical brain tissues showed elevated PSMB4 expression in GBM tissues compared with normal brain tissues. The PSMB4 inhibition decreased proliferation, migration and invasion abilities in human GBM cells. Downregulated PSMB4 resulted in cell cycle arrest and apoptosis in vitro. In an orthotropic xenograft mouse model, the glioma tumors progression was reduced when PSMB4 was down-regulated. The decreased PSMB4 enhanced the anti-tumor effect of temozolomide (TMZ) on tumor growth. In addition, the absence of PSMB4 decreased the expression of phosphorylated focal adhesion kinase and matrix metallopeptidase 9 in vivo. Conclusion: PSMB4 inhibition in combination with TMZ may exert an anti-tumor effect by decreasing cell proliferation and invasion as well as by promoting apoptosis in human glioblastoma cells. This research may improve the therapeutic efficacy of glioblastoma treatment.

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Jinlong capsule inhibits migration and invasion in human glioblastoma cells via the modulation of mTOR/S6 signaling pathway

Drug Design Development and Therapy ◽

10.2147/dddt.s195409 ◽

2019 ◽

Vol Volume 13 ◽

pp. 1023-1032 ◽

Cited By ~ 1

Author(s):

Jingren Shi ◽

Wenli Zhang ◽

Lu He ◽

Fanhong Kong ◽

Meichen Pan ◽

...

Keyword(s):

Signaling Pathway ◽

Migration And Invasion ◽

Glioblastoma Cells ◽

Human Glioblastoma ◽

Human Glioblastoma Cells

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Shikonin Inhibits the Migration and Invasion of Human Glioblastoma Cells by Targeting Phosphorylated β-Catenin and Phosphorylated PI3K/Akt: A Potential Mechanism for the Anti-Glioma Efficacy of a Traditional Chinese Herbal Medicine

International Journal of Molecular Sciences ◽

10.3390/ijms161023823 ◽

2015 ◽

Vol 16 (10) ◽

pp. 23823-23848 ◽

Cited By ~ 36

Author(s):

Feng-Ying Zhang ◽

Yi Hu ◽

Zhong-You Que ◽

Ping Wang ◽

Yun-Hui Liu ◽

...

Keyword(s):

Herbal Medicine ◽

Chinese Herbal Medicine ◽

Migration And Invasion ◽

Potential Mechanism ◽

Glioblastoma Cells ◽

Human Glioblastoma ◽

Traditional Chinese Herbal Medicine ◽

Chinese Herbal ◽

Human Glioblastoma Cells

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Proliferative and Invasive Effects of Progesterone-Induced Blocking Factor in Human Glioblastoma Cells

BioMed Research International ◽

10.1155/2017/1295087 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 11

Author(s):

Araceli Gutiérrez-Rodríguez ◽

Valeria Hansberg-Pastor ◽

Ignacio Camacho-Arroyo

Keyword(s):

Migration And Invasion ◽

Glioblastoma Cells ◽

Human Glioblastoma ◽

Astrocytoma Cells ◽

Blocking Factor ◽

Human Glioblastoma Cells ◽

U87 Cells ◽

Antagonist Ru486 ◽

Human Astrocytoma Cells ◽

Invasion Assays

Progesterone-induced blocking factor (PIBF) is a progesterone (P4) regulated protein expressed in different types of high proliferative cells including astrocytomas, the most frequent and aggressive brain tumors. It has been shown that PIBF increases the number of human astrocytoma cells. In this work, we evaluated PIBF regulation by P4 and the effects of PIBF on proliferation, migration, and invasion of U87 and U251 cells, both derived from human glioblastomas. PIBF mRNA expression was upregulated by P4 (10 nM) from 12 to 24 h. Glioblastoma cells expressed two PIBF isoforms, 90 and 57 kDa. The content of the shorter isoform was increased by P4 at 24 h, while progesterone receptor antagonist RU486 (10 μM) blocked this effect. PIBF (100 ng/mL) increased the number of U87 cells on days 4 and 5 of treatment and induced cell proliferation on day 4. Wound-healing assays showed that PIBF increased the migration of U87 (12–48 h) and U251 (24 and 48 h) cells. Transwell invasion assays showed that PIBF augmented the number of invasive cells in both cell lines at 24 h. These data suggest that PIBF promotes proliferation, migration, and invasion of human glioblastoma cells.

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