Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors.
Armento, Angela; ILINA, Elena; Kaoma, Tonyet al.
2017 • In International Journal of Oncology, 51 (2), p. 702-714
[en] Glioblastoma (GBM), the most frequent and aggressive malignant primary brain tumor, is characterized by a highly invasive growth. In our previous study we showed that overexpression of Carboxypeptidase E (CPE) mitigated glioma cell migration. In the present study we aimed at deciphering the regulatory mechanisms of the secreted form of CPE (sCPE). By transcriptome analysis and inhibition of signaling pathways involved in the regulation of cell growth and motility, we discovered that overexpression of sCPE was accompanied by differential regulation of mRNAs connected to the motility-associated networks, among others FAK, PAK, Cdc42, integrin, STAT3 as well as TGF-β. Especially SLUG was downregulated in sCPE-overexpressing glioma cells, paralleled by reduced expression of matrix-metalloproteinases (MMP) and, in consequence, by decreased cell migration. Expression of SLUG was regulated by ERK since inhibition of ERK reverted sCPE-mediated SLUG downregulation and enhanced cell motility. In a mouse glioma model, overexpression of sCPE significantly prolonged survival. Our results implicate a novel role for sCPE that mainly affects the expression of motility-associated genes via several signal pathways.
Disciplines :
Oncologie
Auteur, co-auteur :
Armento, Angela; Molecular Neuro-Oncology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany.
ILINA, Elena ; Luxembourg Centre of Neuropathology (LCNP), L-3555 Dudelange, Luxembourg.
Kaoma, Tony; Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.), L-1526 Luxembourg, Luxembourg.
Muller, Arnaud; Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.), L-1526 Luxembourg, Luxembourg.
Vallar, Laurent; Genomics and Proteomics Research Unit, Department of Oncology, Luxembourg Institute of Health (L.I.H.), L-1526 Luxembourg, Luxembourg.
NICLOU, Simone P. ; NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health, L-1526 Luxembourg, Luxembourg.
Krüger, Marcel A; Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, D-72076 Tübingen, Germany.
MITTELBRONN, Michel ; Luxembourg Centre of Neuropathology (LCNP), L-3555 Dudelange, Luxembourg.
Naumann, Ulrike; Molecular Neuro-Oncology, Hertie Institute for Clinical Brain Research and Center Neurology, University of Tübingen, D-72076 Tübingen, Germany.
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Carboxypeptidase E transmits its anti-migratory function in glioma cells via transcriptional regulation of cell architecture and motility regulating factors.
Zhong J, Paul A, Kellie SJ and O'Neill GM: Mesenchymal migration as a therapeutic target in glioblastoma. J Oncol 2010: 430142, 2010.
Phillips HS, Kharbanda S, Chen R., Forrest WF, Soriano RH, Wu TD, Misra A, Nigro J.M., Colman H., Soroceanu L, et al.: Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9: 157-173, 2006.
Iser IC, Pereira MB, Lenz G and Wink MR: The epithelial-to-mesenchymal transition-like process in glioblastoma: An updated systematic review and in silico investigation. Med Res Rev 37: 271-313, 2016
Naumann U, Harter PN, Rubel J, Ilina E, Blank AE, Esteban H and Mittelbronn M: Glioma cell migration and invasion as potential target for novel treatment strategies. Transl Neurosci 4: 314-329, 2013.
Cawley NX, Wetsel WC, Murthy S.R., Park JJ, Pacak K and Loh YP: New roles of carboxypeptidase E in endocrine and neural function and cancer. Endocr Rev 33: 216-253, 2012
Lee TK, Murthy SR, Cawley NX, Dhanvantari S, Hewitt SM, Lou H, Lau T, Ma S, Huynh T, Wesley RA, et al.: An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers. J Clin Invest 121: 880-892, 2011
Höring E, Harter PN, Seznec J, Schittenhelm J, Bühring HJ, Bhattacharyya S, Von hattingen E, Zachskorn C, Mittelbronn M and Naumann U: The 'go or grow' potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress. Acta Neuropathol 124: 83-97, 2012.
Murthy SR, Thouennon E, Li W.S., Cheng Y., Bhupatkar J, Cawley NX, Lane M, Merchenthaler I and Loh YP: Carboxypeptidase E protects hippocampal neurons during stress in male mice by up-regulating prosurvival BCL2 protein expression. Endocrinology 154: 3284-3293, 2013
Weiler M, Bähr O, Hohlweg U, Naumann U, Rieger J, Huang H, Tabatabai G, Krell HW, Ohgaki H, Weller M, et al.: BCL-xL Time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells. Cell Death Differ 13: 1156-1169, 2006
Yang HW, Menon LG, Black PM, Carroll RS and Johnson MD: SNAI2/Slug promotes growth and invasion in human gliomas. BMC Cancer 10: 301, 2010.
Naumann U, Kügler S, Wolburg H., Wick W, Rascher G, Schulz J.B., Conseiller E., Bähr M and Weller M: Chimeric tumor suppressor 1, a p53-derived chimeric tumor suppressor gene, kills p53 mutant and p53 wild-type glioma cells in synergy with irradiation and CD95 ligand. Cancer Res 61: 5833-5842, 2001.
He TC, Zhou S, Da Costa LT, Yu J, Kinzler KW and Vogelstein B: A simplifed system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 95: 2509-2514, 1998.
Naumann U, Huang H, Wolburg H., Wischhusen J, Weit S, Ohgaki H and Weller M: PCTAIRE3: A putative mediator of growth arrest and death induced by CTS-1, a dominant-positive p53-derived synthetic tumor suppressor, in human malignant glioma cells. Cancer Gene Ther 13: 469-478, 2006.
Benjamini Y and Hochberg Y: Controlling the false discovery rate: A practical and powerfull approach to multiple testing. J R Stat Soc B 57: 289-300, 1995.
Giese A, Loo MA, Tran N, Haskett D., Coons SW and Berens ME: Dichotomy of astrocytoma migration and proliferation. Int J Cancer 67: 275-282, 1996.
Bernardo MM and Fridman R: TIMP-2 (tissue inhibitor of metal-loproteinase-2) regulates MMP-2 (matrix metalloproteinase-2) activity in the extracellular environment after pro-MMP-2 activation by MT1 (membrane type 1)-MMP. Biochem J 374: 739-745, 2003.
Murthy SR, Dupart E, Al-Sweel N, Chen A., Cawley NX and Loh YP: Carboxypeptidase E promotes cancer cell survival, but inhibits migration and invasion. Cancer Lett 341: 204-213, 2013.
Verbovšek U., Motaln H, Rotter A., Atai NA, Gruden K, Van Noorden CJ and Lah TT: Expression analysis of all protease genes reveals cathepsin K to be overexpressed in glioblastoma. PLoS One 9: e111819, 2014.
Cheng Y, Cawley NX and Loh YP: Carboxypeptidase E/NFα1: A new neurotrophic factor against oxidative stress-induced apoptotic cell death mediated by ERK and PI3-K/AKT pathways. PLoS One 8: e71578, 2013.
Skalka N, Caspi M, Caspi E., Loh YP and Rosin-Arbesfeld R: Carboxypeptidase E: A negative regulator of the canonical Wnt signaling pathway. Oncogene 32: 2836-2847, 2013.
Jeibmann A, Halama K, Witte H.T., Kim SN, Eikmeier K, Koos B, Klämbt C and Paulus W: Involvement of CD9 and PDGFR in migration is evolutionarily conserved from Drosophila glia to human glioma. J Neurooncol 124: 373-383, 2015.
Sobczak M, Boczek T, Ferenc B., Taha J, Kozaczuk A, Wiktorska M., Sacewicz-hofman I, Niewiarowska J and Zylinska L: Functional characteristic of PC12 cells with reduced microsomal glutathione transferase 1. Acta Biochim Pol 57: 589-596, 2010.
Haruki S, Imoto I, Kozaki K., Matsui T, Kawachi H, Komatsu S., Muramatsu T, Shimada Y, Kawano T and Inazawa J: Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous cell carcinoma. Carcinogenesis 31: 1027-1036, 2010.
Dang Z, Shangguan J, Zhang C., Hu P, Ren Y, Lv Z., Xiang H and Wang X: Loss of protocadherin-17 (PCDh-17) promotes metastasis and invasion through hyperactivation of EGFR/MEK/ERK signaling pathway in hepatocellular carcinoma. Tumour Biol 37: 2527-2535, 2016.
Held-Feindt J., Paredes EB, Blömer U, Seidenbecher C., Stark AM, Mehdorn HM and Mentlein R: Matrix-degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metal-loproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas. Int J Cancer 118: 55-61, 2006.
Lee JK, Joo KM, Lee J, Yoon Y and Nam DH: Targeting the epithelial to mesenchymal transition in glioblastoma: The emerging role of MET signaling. Onco Targets Ther 7: 1933-1944, 2014.
Lu DY, Yeh WL, Huang S.M., Tang CH, Lin HY and Chou SJ: Osteopontin increases heme oxygenase-1 expression and subsequently induces cell migration and invasion in glioma cells. Neuro-oncol 14: 1367-1378, 2012.
Potapenko IO, Haakensen VD, Lüders T, Helland A., Bukholm I, Sørlie T, Kristensen VN, Lingjaerde OC and Børresen-Dale AL: Glycan gene expression signatures in normal and malignant breast tissue; possible role in diagnosis and progression. Mol Oncol 4: 98-118, 2010.
Niimi K, Yamamoto E, Fujiwara S., Shinjo K, Kotani T, Umezu T., Kajiyama H, Shibata K, Ino K and Kikkawa F: high expression of N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma. Br J Cancer 107: 1969-1977, 2012.
Fan J, Wang S, Yu S., He J, Zheng W and Zhang J: N-acetyl-glucosaminyltransferase IVa regulates metastatic potential of mouse hepatocarcinoma cells through glycosylation of CD147. Glycoconj J 29: 323-334, 2012.
Ide Y, Miyoshi E, Nakagawa T., Gu J, Tanemura M, Nishida T., Ito T, Yamamoto H, Kozutsumi Y and Taniguchi N: Aberrant expression of N-acetylglucosaminyltransferase-IVa and IVb (GnT-IVa and b) in pancreatic cancer. Biochem Biophys Res Commun 341: 478-482, 2006.
Tania M, Khan MA and Fu J: Epithelial to mesenchymal transition inducing transcription factors and metastatic cancer. Tumour Biol 35: 7335-7342, 2014.
Kahlert UD, Nikkhah G and Maciaczyk J: Epithelial-to-mesenchymal(-like) transition as a relevant molecular event in malignant gliomas. Cancer Lett 331: 131-138, 2013.
Chesnelong C and Luchman AH: STAT3 is a key regulator of an 'EMT-like' process mediated by Slug in GBM. Cancer Res 76: 2524, 2016.
Iwadate Y: Epithelial-mesenchymal transition in glioblastoma progression. Oncol Lett 11: 1615-1620, 2016.
Shih JY and Yang PC: The EMT regulator slug and lung carcino-genesis. Carcinogenesis 32: 1299-1304, 2011.
Geismann C, Arlt A, Bauer I., Pfeifer M, Schirmer U, Altevogt P., Müerköster SS and Schäfer H: Binding of the transcription factor Slug to the L1CAM promoter is essential for transforming growth factor-β1 (TGF-β)-induced L1CAM expression in human pancreatic ductal adenocarcinoma cells. Int J Oncol 38: 257-266, 2011.
Yang M, Li Y, Chilukuri K., Brady OA, Boulos MI, Kappes JC and Galileo DS: L1 stimulation of human glioma cell motility correlates with FAK activation. J Neurooncol 105: 27-44, 2011.
Lamouille S, Xu J and Derynck R: Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15: 178-196, 2014.
Nagaishi M, Paulus W, Brokinkel B., Vital A, Tanaka Y, Nakazato Y., Giangaspero F and Ohgaki H: Transcriptional factors for epithelial-mesenchymal transition are associated with mesenchymal differentiation in gliosarcoma. Brain Pathol 22: 670-676, 2012.
Goldberg L and Kloog Y: A Ras inhibitor tilts the balance between Rac and Rho and blocks phosphatidylinositol 3-kinase-dependent glioblastoma cell migration. Cancer Res 66: 11709-11717, 2006.
Stepanenko AA, Andreieva SV, Korets K.V., Mykytenko DO, Baklaushev V P, Chekhonin VP and Dmitrenko VV: mTOR inhibitor temsirolimus and MEK1/2 inhibitor U0126 promote chromosomal instability and cell type-dependent phenotype changes of glioblastoma cells. Gene 579: 58-68, 2016.
Skalka N, Caspi M, Lahav-Ariel L, Loh Y.P., Hirschberg K., Rosin-Arbesfeld R and Carboxypeptidase E: Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a. Oncogene 35: 6416-6428, 2016.
Arnaoutova I, Jackson CL, Al-Awar OS, Donaldson JG and Loh YP: Recycling of Raft-associated prohormone sorting receptor carboxypeptidase E requires interaction with ARF6. Mol Biol Cell 14: 4448-4457, 2003.
Sabe H: Requirement for Arf6 in cell adhesion, migration, and cancer cell invasion. J Biochem 134: 485-489, 2003.
