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The transcription factor ERG increases expression of neurotransmitter receptors on prostate cancer cells.

ABSTRACT: The TMPRSS2-ERG gene fusion occurs in about half of prostate cancer (PCa) cases and results in overexpression of the transcription factor ERG. Overexpression of ERG has many effects on cellular function. However, how these changes enhance cell growth and promote tumor development is unclear.To investigate the role of ERG, LNCaP and PC3 cells were transfected with ERG and gene expression and metabolic profile were analyzed.Our data show that expression of ERG induces overexpression of many nicotinicacetylcholine receptors (nAChRs). In addition, metabolic profiling by LC-MS/MS revealed elevated production of several neurotransmitters in cells expressing ERG. Consistently, treatment of ERG-expressing cells with nicotine induced elevated calcium influx, GSK3? (Ser9) phosphorylation and cell proliferation. Finally, we show that PCa patientswho are smokers have larger tumors if their tumors are TMPRSS2-ERG gene fusion positive.Collectively, our data suggest that ERG sensitizes prostate tumor cells to neurotransmitter receptor agonists like nicotine.

SUBMITTER: Kissick HT

PROVIDER: S-EPMC4549934 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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The transcription factor ERG increases expression of neurotransmitter receptors on prostate cancer cells.

Kissick Haydn T HT On Seung T ST Dunn Laura K LK Sanda Martin G MG Asara John M JM Pellegrini Kathryn L KL Noel Jonathan K JK Arredouani Mohamed S MS

BMC cancer 20150827

<h4>Background</h4>The TMPRSS2-ERG gene fusion occurs in about half of prostate cancer (PCa) cases and results in overexpression of the transcription factor ERG. Overexpression of ERG has many effects on cellular function. However, how these changes enhance cell growth and promote tumor development is unclear.<h4>Methods</h4>To investigate the role of ERG, LNCaP and PC3 cells were transfected with ERG and gene expression and metabolic profile were analyzed.<h4>Results</h4>Our data show that expr ...[more]

PMID: 26310325

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Project description:The incidence and mortality rates of prostate cancer (PCa) are increasing, and PCa is almost the second?leading cause of cancer?associated mortality in men. During tumor progression, epithelial cells decrease the number of adhesion molecules, change their polarity and position, rearrange their cytoskeleton and increase their migratory and invasive capacities. These changes are known under the concept of epithelial?mesenchymal transition (EMT). EMT is characterized by an upregulation of certain transcription factors, including SNAIL1, which represses genes that are characteristic of an epithelial phenotype, including E?cadherin, and indirectly increase the expression levels of genes, which are associated with the mesenchymal phenotype. It has been suggested that the transcription factor, SNAIL1, decreases the proliferation and increases the migratory and invasive capacities of PCa cell lines. The present study was performed using LNCaP and PC3 cell lines, in which the expression levels of SNAIL1 were increased or silenced through the use of lentiviral vectors. The expression levels of EMT markers were quantified using reverse transcription?quantitative polymerase chain reaction and western blot analysis. In addition, cell survival was analyzed using an MTS assay; cell proliferation was examined using an antibody targeting Ki?67; migration on plates with 8 µm pores to allow the passage of cells; and invasiveness was analyzed using a membrane chamber covered in dried basement membrane matrix solution. The levels of apoptosis were determined using a Caspase 3/7 assay containing a substrate modified by caspases 3 and 7. The results demonstrated that the overexpression and silencing of SNAIL1 decreased cell proliferation and survival. However, the overexpression of SNAIL1 decreased apoptosis, compared with cells with the SNAIL1?silenced cells, in which cell apoptosis increased. The migration and invasive capacities increased in the cells overexpressing SNAIL1, and decreased when SNAIL1 was silenced. In conclusion, PCa cells overexpressing SNAIL1 exhibited characteristics of an EMT phenotype, whereas the silencing of the SNAIL1 transcriptional repressor promoted an epithelial?like phenotype, with decreased migration and invasion, characteristic of mesenchymal cells.

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The transcription factor ERG increases expression of neurotransmitter receptors on prostate cancer cells.

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The transcription factor ERG increases expression of neurotransmitter receptors on prostate cancer cells.

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