Artikel
Functional and pathological insights of Carboxypeptidase E (CPE) effects on glioblastoma “go or grow” behavior
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Autoren
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Elena Ilina
- Goethe University, Edinger Institute (Neurological Institute), Frankfurt, Germany
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Angela Armento
- Hertie Institute for Clinical Brain Research, Molecular Neurooncology, Tübingen, Germany
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Lukas Jennewein
- Goethe University, Edinger Institute (Neurological Institute), Frankfurt, Germany
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Cornelia Penski
- Goethe University, Edinger Institute (Neurological Institute), Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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Sven Zukunft
- Goethe University, Institute for Vascular Signaling, Centre for Molecular Medicine, Frankfurt, Germany
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Christian Behrends
- Medical School Goethe University, Institute of Biochemistry II, Frankfurt, Germany
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Michael Ronellenfitsch
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Goethe University, Senckenberg Institute of Neurooncology, Frankfurt, Germany
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Kavi Devraj
- Goethe University, Edinger Institute (Neurological Institute), Frankfurt, Germany
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Anne Braczynski
- Goethe University, Edinger Institute (Neurological Institute), Frankfurt, Germany
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Karl Plate
- Goethe University, Edinger Institute (Neurological Institute), Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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Patrick Harter
- Goethe University, Edinger Institute (Neurological Institute), Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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Ulrike Naumann
- Hertie Institute for Clinical Brain Research, Molecular Neurooncology, Tübingen, Germany
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Michel Mittelbronn
- Goethe University, Edinger Institute (Neurological Institute), Frankfurt, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| Veröffentlicht: | 25. August 2015 |
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Gliederung
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Introduction: Glioblastoma (GBM) is the most common malignant brain tumor with a poor prognosis characterized by an extreme invasive potential. This hallmark of GBM is implicated into a so called „go or grow“ hypothesis: a behavior of tumor cells that describes their switch between proliferation and migration. In our previous study, we showed that overexpression of Carboxypeptidase E (CPE) mitigated migration, however enhanced proliferation. These effects were associated with the secreted form of CPE (sCPE).
Objectives: In our current study we aim at deciphering the regulatory mechanisms of sCPE and understanding their clinical relevance.
Materials and methods: The human LNT229 GBM cell line was transfected with pcDNA3-CPE vector. An empty pcDNA3 was used as a control. mRNA screening was utilized to identify genes that are regulated by CPE. Western blot, immunohistochemistry and qRT-PCR were used to examine the activation of Erk1/2, Akt and STAT3 pathways and to assess the expression of metabolic-related proteins and genes. Alterations in cellular metabolism were investigated by mass-spectrometry. To assess radio- and chemosensitivity, irradiation and TMZ-treatment were used.
Results: Here we show, that increased amounts of sCPE led to increased activity of the MAPK and PI3K/Akt pathways, mitigated STAT3 signaling propagation and altered the expression of numerous genes, involved in cellular migration and adhesion (e.g. SNAI2, SPP1), cell cycle regulation (e.g. CCNB3, CCNB2), signal transduction (e.g. ENPP2, DUSP2) and metabolism (e.g. PRKAA2). Cells with higher sCPE levels also showed increased sensitivity towards irradiation and chemotherapy. In addition, analysis of glycolysis and Krebs cycle suggested that the switch between migration and proliferation might be partly linked to a modulation of glucose metabolism, which may provide a beneficial energy supply as well as necessary intermediates for nucleic acid and cellular membrane synthesis.
Conclusion: These results implicate that CPE may affect several cancerogenic pathways. Thus, an advanced of the mechanisms by which CPE modulates proliferation and migration might shed light on what drives glioma cells to stay or to expand under different conditions. These insights might be beneficial for future therapeutic strategies aimed at treating GBM.
