Skip to main content
Erschienen in: Cancer Microenvironment 1-3/2017

18.08.2017 | Original Article

Expression Profiling of the MAP Kinase Phosphatase Family Reveals a Role for DUSP1 in the Glioblastoma Stem Cell Niche

verfasst von: Bradley N. Mills, George P. Albert, Marc W. Halterman

Erschienen in: Cancer Microenvironment | Ausgabe 1-3/2017

Einloggen, um Zugang zu erhalten

Abstract

The dual specificity phosphatases (DUSPs) constitute a family of stress-induced enzymes that provide feedback inhibition on mitogen-activated protein kinases (MAPKs) critical in key aspects of oncogenic signaling. While described in other tumor types, the landscape of DUSP mRNA expression in glioblastoma (GB) remains largely unexplored. Interrogation of the REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT) revealed induction (DUSP4, DUSP6), repression (DUSP2, DUSP7–9), or mixed (DUSP1, DUSP5, DUSP10, DUSP15) DUSP transcription of select DUSPs in bulk tumor specimens. To resolve features specific to the tumor microenvironment, we searched the Ivy Glioblastoma Atlas Project (Ivy GAP) repository, which highlight DUSP1, DUSP5, and DUSP6 as the predominant family members induced within pseudopalisading and perinecrotic regions. The inducibility of DUSP1 in response to hypoxia, dexamethasone, or the chemotherapeutic agent camptothecin was confirmed in GB cell lines and tumor-derived stem cells (TSCs). Moreover, we show that loss of DUSP1 expression is a characteristic of TSCs and correlates with expression of tumor stem cell markers in situ (ABCG2, PROM1, L1CAM, NANOG, SOX2). This work reveals a dynamic pattern of DUSP expression within the tumor microenvironment that reflects the cumulative effects of factors including regional ischemia, chemotherapeutic exposure among others. Moreover, our observation regarding DUSP1 dysregulation within the stem cell niche argue for its importance in the survival and proliferation of this therapeutically resistant population.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Rong Y et al (2006) 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65(6):529–539CrossRefPubMed Rong Y et al (2006) 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol 65(6):529–539CrossRefPubMed
2.
Zurück zum Zitat Persano L et al (2011) The three-layer concentric model of glioblastoma: cancer stem cells, microenvironmental regulation, and therapeutic implications. Sci World J 11:1829–1841CrossRef Persano L et al (2011) The three-layer concentric model of glioblastoma: cancer stem cells, microenvironmental regulation, and therapeutic implications. Sci World J 11:1829–1841CrossRef
3.
Zurück zum Zitat Vartanian A et al (2014) GBM's multifaceted landscape: highlighting regional and microenvironmental heterogeneity. Neuro-Oncology 16(9):1167–1175CrossRefPubMedPubMedCentral Vartanian A et al (2014) GBM's multifaceted landscape: highlighting regional and microenvironmental heterogeneity. Neuro-Oncology 16(9):1167–1175CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Li Z et al. (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. In: Cancer Cell. Elsevier Ltd. p 501–513 Li Z et al. (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. In: Cancer Cell. Elsevier Ltd. p 501–513
6.
Zurück zum Zitat Vitucci M et al (2013) Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis. Neuro-Oncology 15(10):1317–1329CrossRefPubMedPubMedCentral Vitucci M et al (2013) Cooperativity between MAPK and PI3K signaling activation is required for glioblastoma pathogenesis. Neuro-Oncology 15(10):1317–1329CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Raman M, Chen W, Cobb MH (2007) Differential regulation and properties of MAPKs. Oncogene 26(22):3100–3112CrossRefPubMed Raman M, Chen W, Cobb MH (2007) Differential regulation and properties of MAPKs. Oncogene 26(22):3100–3112CrossRefPubMed
8.
Zurück zum Zitat Boutros T, Chevet E, Metrakos P (2008) Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev 60(3):261–310CrossRefPubMed Boutros T, Chevet E, Metrakos P (2008) Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev 60(3):261–310CrossRefPubMed
9.
Zurück zum Zitat De Witt Hamer PC (2010) Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies. Neuro-Oncology 12(3):304–316CrossRefPubMedPubMedCentral De Witt Hamer PC (2010) Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies. Neuro-Oncology 12(3):304–316CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Yu H et al (2012) Constitutive expression of MAP kinase phosphatase-1 confers multi-drug resistance in human glioblastoma cells. Cancer Res Treat 44(3):195–201CrossRefPubMedPubMedCentral Yu H et al (2012) Constitutive expression of MAP kinase phosphatase-1 confers multi-drug resistance in human glioblastoma cells. Cancer Res Treat 44(3):195–201CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Messina S et al (2011) Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas. Oncogene 30(35):3813–3820CrossRefPubMed Messina S et al (2011) Dual-specificity phosphatase DUSP6 has tumor-promoting properties in human glioblastomas. Oncogene 30(35):3813–3820CrossRefPubMed
12.
Zurück zum Zitat Waha A et al (2010) Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells. Cancer Res 70(4):1689–1699CrossRefPubMed Waha A et al (2010) Epigenetic downregulation of mitogen-activated protein kinase phosphatase MKP-2 relieves its growth suppressive activity in glioma cells. Cancer Res 70(4):1689–1699CrossRefPubMed
13.
Zurück zum Zitat Wayne J et al (2006) ERK regulation upon contact inhibition in fibroblasts. Mol Cell Biochem 286(1–2):181–189CrossRefPubMed Wayne J et al (2006) ERK regulation upon contact inhibition in fibroblasts. Mol Cell Biochem 286(1–2):181–189CrossRefPubMed
14.
Zurück zum Zitat Sakaue H et al (2004) Role of MAPK phosphatase-1 (MKP-1) in adipocyte differentiation. J Biol Chem 279(38):39951–39957CrossRefPubMed Sakaue H et al (2004) Role of MAPK phosphatase-1 (MKP-1) in adipocyte differentiation. J Biol Chem 279(38):39951–39957CrossRefPubMed
15.
Zurück zum Zitat Laderoute KR et al (1999) Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments. A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity. J Biol Chem 274(18):12890–12897CrossRefPubMed Laderoute KR et al (1999) Mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is induced by low oxygen conditions found in solid tumor microenvironments. A candidate MKP for the inactivation of hypoxia-inducible stress-activated protein kinase/c-Jun N-terminal protein kinase activity. J Biol Chem 274(18):12890–12897CrossRefPubMed
16.
Zurück zum Zitat Lin YM et al (2008) Dexamethasone reduced invasiveness of human malignant glioblastoma cells through a MAPK phosphatase-1 (MKP-1) dependent mechanism. Eur J Pharmacol 593(1–3):1–9CrossRefPubMed Lin YM et al (2008) Dexamethasone reduced invasiveness of human malignant glioblastoma cells through a MAPK phosphatase-1 (MKP-1) dependent mechanism. Eur J Pharmacol 593(1–3):1–9CrossRefPubMed
18.
Zurück zum Zitat Zhang Y et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947CrossRefPubMedPubMedCentral Zhang Y et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36):11929–11947CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Galli R et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021CrossRefPubMed Galli R et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021CrossRefPubMed
22.
Zurück zum Zitat Inuzuka H et al (1999) Differential regulation of immediate early gene expression in preadipocyte cells through multiple signaling pathways. Biochem Biophys Res Commun 265(3):664–668CrossRefPubMed Inuzuka H et al (1999) Differential regulation of immediate early gene expression in preadipocyte cells through multiple signaling pathways. Biochem Biophys Res Commun 265(3):664–668CrossRefPubMed
23.
Zurück zum Zitat Sahu M, Mallick B (2016) An integrative approach predicted co-expression sub-networks regulating properties of stem cells and differentiation. Comput Biol Chem 64:250–262CrossRefPubMed Sahu M, Mallick B (2016) An integrative approach predicted co-expression sub-networks regulating properties of stem cells and differentiation. Comput Biol Chem 64:250–262CrossRefPubMed
24.
Zurück zum Zitat Boulding T et al (2016) Differential roles for DUSP family members in epithelial-to-mesenchymal transition and cancer stem cell regulation in breast cancer. PLoS One 11(2):e0148065CrossRefPubMedPubMedCentral Boulding T et al (2016) Differential roles for DUSP family members in epithelial-to-mesenchymal transition and cancer stem cell regulation in breast cancer. PLoS One 11(2):e0148065CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Bleau AM, Huse JT, Holland EC (2009) The ABCG2 resistance network of glioblastoma. Cell Cycle 8(18):2936–2944CrossRefPubMed Bleau AM, Huse JT, Holland EC (2009) The ABCG2 resistance network of glioblastoma. Cell Cycle 8(18):2936–2944CrossRefPubMed
28.
Zurück zum Zitat Martinez-Lozada Z et al (2014) Activation of sodium-dependent glutamate transporters regulates the morphological aspects of oligodendrocyte maturation via signaling through calcium/calmodulin-dependent kinase IIbeta's actin-binding/−stabilizing domain. Glia 62(9):1543–1558CrossRefPubMedPubMedCentral Martinez-Lozada Z et al (2014) Activation of sodium-dependent glutamate transporters regulates the morphological aspects of oligodendrocyte maturation via signaling through calcium/calmodulin-dependent kinase IIbeta's actin-binding/−stabilizing domain. Glia 62(9):1543–1558CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Roybon L et al (2009) Neurogenin2 directs granule neuroblast production and amplification while NeuroD1 specifies neuronal fate during hippocampal neurogenesis. PLoS One 4(3):e4779CrossRefPubMedPubMedCentral Roybon L et al (2009) Neurogenin2 directs granule neuroblast production and amplification while NeuroD1 specifies neuronal fate during hippocampal neurogenesis. PLoS One 4(3):e4779CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Shen WH et al (2006) Mitogen-activated protein kinase phosphatase 2: a novel transcription target of p53 in apoptosis. Cancer Res 66(12):6033–6039CrossRefPubMed Shen WH et al (2006) Mitogen-activated protein kinase phosphatase 2: a novel transcription target of p53 in apoptosis. Cancer Res 66(12):6033–6039CrossRefPubMed
31.
Zurück zum Zitat Li M et al (2003) The phosphatase MKP1 is a transcriptional target of p53 involved in cell cycle regulation. J Biol Chem 278(42):41059–41068CrossRefPubMed Li M et al (2003) The phosphatase MKP1 is a transcriptional target of p53 involved in cell cycle regulation. J Biol Chem 278(42):41059–41068CrossRefPubMed
32.
Zurück zum Zitat Liu YX et al (2008) DUSP1 is controlled by p53 during the cellular response to oxidative stress. Mol Cancer Res 6(4):624–633CrossRefPubMed Liu YX et al (2008) DUSP1 is controlled by p53 during the cellular response to oxidative stress. Mol Cancer Res 6(4):624–633CrossRefPubMed
33.
Zurück zum Zitat Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481(7381):287–294CrossRefPubMed Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481(7381):287–294CrossRefPubMed
34.
Zurück zum Zitat Esteller M et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343(19):1350–1354CrossRefPubMed Esteller M et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343(19):1350–1354CrossRefPubMed
35.
Zurück zum Zitat Hegi ME et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003CrossRefPubMed Hegi ME et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003CrossRefPubMed
36.
Zurück zum Zitat Ferguson BS et al (2016) Mitogen-dependent regulation of DUSP1 governs ERK and p38 signaling during early 3T3-L1 adipocyte differentiation. J Cell Physiol 231(7):1562–1574CrossRefPubMed Ferguson BS et al (2016) Mitogen-dependent regulation of DUSP1 governs ERK and p38 signaling during early 3T3-L1 adipocyte differentiation. J Cell Physiol 231(7):1562–1574CrossRefPubMed
38.
Zurück zum Zitat Li Z, Theus MH, Wei L (2006) Role of ERK 1/2 signaling in neuronal differentiation of cultured embryonic stem cells. Develop Growth Differ 48(8):513–523CrossRef Li Z, Theus MH, Wei L (2006) Role of ERK 1/2 signaling in neuronal differentiation of cultured embryonic stem cells. Develop Growth Differ 48(8):513–523CrossRef
39.
Zurück zum Zitat Wu JJ et al (2006) Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Cell Metab 4(1):61–73CrossRefPubMed Wu JJ et al (2006) Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity. Cell Metab 4(1):61–73CrossRefPubMed
40.
Zurück zum Zitat Meletis K et al (2006) p53 suppresses the self-renewal of adult neural stem cells. Development 133(2):363–369CrossRefPubMed Meletis K et al (2006) p53 suppresses the self-renewal of adult neural stem cells. Development 133(2):363–369CrossRefPubMed
41.
Zurück zum Zitat Cancer Genome Atlas Research, N (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068CrossRef Cancer Genome Atlas Research, N (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068CrossRef
42.
Zurück zum Zitat Li J et al (2001) Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation. Mol Cell Biol 21(23):8213–8224CrossRefPubMedPubMedCentral Li J et al (2001) Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation. Mol Cell Biol 21(23):8213–8224CrossRefPubMedPubMedCentral
43.
Zurück zum Zitat Brondello J (1999) Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286(5449):2514–2517CrossRefPubMed Brondello J (1999) Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286(5449):2514–2517CrossRefPubMed
Metadaten
Titel
Expression Profiling of the MAP Kinase Phosphatase Family Reveals a Role for DUSP1 in the Glioblastoma Stem Cell Niche
verfasst von
Bradley N. Mills
George P. Albert
Marc W. Halterman
Publikationsdatum
18.08.2017
Verlag
Springer Netherlands
Erschienen in
Cancer Microenvironment / Ausgabe 1-3/2017
Print ISSN: 1875-2292
Elektronische ISSN: 1875-2284
DOI
https://doi.org/10.1007/s12307-017-0197-6

Weitere Artikel der Ausgabe 1-3/2017

Cancer Microenvironment 1-3/2017 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.