Gene expression profile in a glioma cell line resistant to cell death induced by a the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53—the role of NFκB

Seznec, Janina; Weit, Simone; Naumann, Ulrike

doi:10.1093/carcin/bgp319

Cited by 16 publications

(19 citation statements)

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“…1a) [30], the fact that CPE mRNA expression was significantly reduced in glioblastomas as compared to normal brain tissue in the TCGA and REMBRANDT databases (Fig. 1b), the function of CPE as a peptidase [7] and the knowledge from the literature that low CPE expression is correlated with tumor malignancy in neuroendocrine tumors [11,12,22] prompted us to analyze whether CPE is involved in glioma malignancy and progression.…”

Section: Discussionmentioning

confidence: 99%

“…Using whole genome microarray expression analysis, we found CPE to be the most differentially regulated gene in LNT-229 Res cells compared to the parental cell line LNT-229 P [30]. Expression of CPE mRNA was 45-fold lower in LNT-229 Res than in LNT-229 P cells (Fig.…”

Section: Cpe Expression Is Reduced In Gliomas and Associated With Shomentioning

confidence: 90%

“…Finally, the analysis of both The Cancer Genome Atlas (TCGA) [33] and the National Cancer Institute (NCI) Repository for Molecular Brain Neoplasia Data Platform (REMBRANDT) revealed that CPE mRNA is significantly downregulated in glioblastomas as compared to normal brain tissue or lower grade gliomas, and might therefore be a so far unidentified tumor suppressor gene. These data and the fact that CPE is downregulated in cell death resistant GBM cells [30] prompted us to analyze whether in GBM CPE might harbor functions of a tumor suppressor by either influencing cell death or tumor cell migration.…”

Section: Introductionmentioning

confidence: 99%

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The “go or grow” potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress

et al. 2012

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Glioblastoma (GBM), the most common malignant brain tumor, is among the most lethal neoplasms, with a median survival of approximately 1 year. Prognosis is poor since GBMs possess a strong migratory and highly invasive potential, making complete surgical resection impossible. Reduced expression of carboxypeptidase E (CPE), a neuropeptide-processing enzyme, in a cell death-resistant glioma cell line and lower CPE expression levels in the cohort of GBM samples of The Cancer Genome Atlas compared to normal brain control specimens prompted us to analyze the function of CPE as a putative tumor suppressor gene. In our samples, CPE was also reduced in GBM compared to normal brain with the strongest loss in cells surrounding hypoxic tumor areas as well as in most glioma cell lines and primary glioma cells. In our cohort of glioma patients, loss of CPE predominantly occurred in glioblastomas and was associated with worse prognosis. In glioma cells, CPE overexpression was significantly reduced, whereas knockdown or inhibition enhanced glioma cell migration and invasion. The decreased migratory potential following CPE overexpression was paralleled by altered cellular morphology, promoting a transition to focal adhesions and associated stress fibers. In contrast to the decreased migration, high CPE levels were associated with higher proliferative rates. As microenvironmental regulation cues, we identified CPE as being downregulated upon hypoxia or glucose deprivation. Our findings indicate an oxygen- and nutrition-dependent anti-migratory, but pro-proliferative role of CPE in gliomas with prognostic impact for patient survival, thereby contributing to the understanding of the "go or grow" hypothesis in gliomas.

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Section: Discussionmentioning

confidence: 99%

Section: Cpe Expression Is Reduced In Gliomas and Associated With Shomentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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The “go or grow” potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress

et al. 2012

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“…In this respect, BEX2 expression protects breast cancer cells against mitochondrial apoptosis and is necessary for the normal transition of these cells through G1 cell cycle [2]. In addition, it has recently been shown that down-regulation of BEX1 and BEX2 sensitize LNT-229 glioma cells to the chimeric tumor suppressor-1 (CST-1), a dominant-positive variant of p53, and up-regulation of BEX1 protects these cells to CST-1-induced cell death [22]. These findings further support a pro-survival function for BEX1 and BEX2 using a glioma model.…”

Section: Discussionmentioning

confidence: 99%

BEX2 has a functional interplay with c-Jun/JNK and p65/RelA in breast cancer

2010

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BackgroundWe have previously demonstrated that BEX2 is differentially expressed in breast tumors and has a significant role in promoting cell survival and growth in breast cancer cells. BEX2 expression protects breast cancer cells against mitochondrial apoptosis and G1 cell cycle arrest. In this study we investigated the transcriptional regulation of BEX2 and feedback mechanisms mediating the cellular function of this gene in breast cancer.ResultsWe found a marked induction of BEX2 promoter by c-Jun and p65/RelA using luciferase reporter assays in MCF-7 cells. Furthermore, we confirmed the binding of c-Jun and p65/RelA to the BEX2 promoter using a chromatin immunoprecipitation assay. Importantly, transfections of c-Jun or p65/RelA in MCF-7 cells markedly increased the expression of BEX2 protein. Overall, these results demonstrate that BEX2 is a target gene for c-Jun and p65/RelA in breast cancer. These findings were further supported by the presence of a strong correlation between BEX2 and c-Jun expression levels in primary breast tumors. Next we demonstrated that BEX2 has a feedback mechanism with c-Jun and p65/RelA in breast cancer. In this process BEX2 expression is required for the normal phosphorylation of p65 and IκBα, and the activation of p65. Moreover, it is necessary for the phosphorylation of c-Jun and JNK kinase activity in breast cancer cells. Furthermore, using c-Jun stable lines we showed that BEX2 expression is required for c-Jun mediated induction of cyclin D1 and cell proliferation. Importantly, BEX2 down-regulation resulted in a significant increase in PP2A activity in c-Jun stable lines providing a possible underlying mechanism for the regulatory effects of BEX2 on c-Jun and JNK.ConclusionsThis study shows that BEX2 has a functional interplay with c-Jun and p65/RelA in breast cancer. In this process BEX2 is a target gene for c-Jun and p65/RelA and in turn regulates the phosphorylation/activity of these proteins. These suggest that BEX2 is involved in a novel feedback mechanism with significant implications for the biology of breast cancer.

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“…cDNA from RNA of 229P and 229R cells, that underwent microarray expression analysis, was examined (Figure 2, [20] and data not shown).…”

Section: Resultsmentioning

confidence: 99%

Microarray Analysis in a Cell Death Resistant Glioma Cell Line to Identify Signaling Pathways and Novel Genes Controlling Resistance and Malignancy

Seznec

Naumann

2011

Cancers

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Glioblastoma multiforme (GBM) is a lethal type of cancer mainly resistant to radio- and chemotherapy. Since the tumor suppressor p53 functions as a transcription factor regulating the expression of genes involved in growth inhibition, DNA repair and apoptosis, we previously assessed whether specific differences in the modulation of gene expression are responsible for the anti-tumor properties of a dominant positive p53, chimeric tumor suppressor (CTS)-1. CTS-1 is based on the sequence of p53 and designed to resist various mechanisms of inactivation which limit the activity of p53. To identify CTS-1-regulated cell death-inducing genes, we generated a CTS-1-resistant glioma cell line (229R). We used Affymetrix whole-genome microarray expression analysis to analyze alterations in gene expression and identified a variety of CTS-1 regulated genes involved in cancer-linked processes. 313 genes were differentially expressed in Adeno-CTS-1 (Ad-CTS-1)-infected and 700 genes in uninfected 229R cells compared to matching parental cells. Ingenuity Pathway Analysis (IPA) determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of the intracellular networks with central tumor-involved players such as nuclear factor kappa B (NF-κB), protein kinase B (PKB/AKT) or transforming growth factor beta (TGF-β). Differentially regulated genes include secreted factors as well as intracellular proteins and transcription factors regulating not only cell death, but also processes such as tumor cell motility and immunity. This work gives an overview of the pathways differentially regulated in the resistant versus parental glioma cells and might be helpful to identify candidate genes which could serve as targets to develop novel glioma specific therapy strategies.

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Gene expression profile in a glioma cell line resistant to cell death induced by a the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53—the role of NFκB

Cited by 16 publications

References 35 publications

The “go or grow” potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress

The “go or grow” potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress

BEX2 has a functional interplay with c-Jun/JNK and p65/RelA in breast cancer

Microarray Analysis in a Cell Death Resistant Glioma Cell Line to Identify Signaling Pathways and Novel Genes Controlling Resistance and Malignancy

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