Top

Published in:

01-02-2011 | Laboratory Investigation - Human/Animal Tissue

Therapeutic effects of the Sp1 inhibitor mithramycin A in glioblastoma

Authors: Janina Seznec, Björn Silkenstedt, Ulrike Naumann

Published in: Journal of Neuro-Oncology | Issue 3/2011

Abstract

Mithramycin A (MitA) is a chemotherapeutic compound which has been used in the therapy of several types of cancer. For experimental cancer it has been shown that MitA mediates the expression of genes involved in tumor progression such as genes involved in immunosurveillance, cell motility or cell death. MitA works synergistically with Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and with antiangiogenic agents. We were therefore interested in analyzing whether MitA might be a suitable agent for glioma therapy. We demonstrate herein that the cell death sensitizing effects of MitA are cell line specific, independent of the endogenous status of the tumor suppressor p53 as well as of the endogenous expression of X-linked inhibitor of apoptosis (XIAP) or basal sensitivity towards death ligand-induced cell death. In glioma cells, MitA reduced the secretion and activity of the migration-involved matrix metalloproteinases (MMP), diminished vascular endothelial growth factor (VEGF), and increased recepteur d’origine nantais (RON) kinase messenger RNA (mRNA), paralleled by a significant reduction of glioma cell migration. In contrast to other cancer types, in glioma cells MitA did not alter the expression of the immunorelevant genes major histocompatibility complex I class related (MIC)-A, MIC-B or UL16 binding proteins (ULBP). We conclude that, whereas MitA-mediated reduction of XIAP expression and sensitization to Apo2L/TRAIL are cell line specific, its antimigratory effects are more general and might be the result of altered expression of MMP, VEGF, and/or RON kinase. Therefore, MitA might be a potential agent to reduce glioma cell migration.

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Engl J Med 352:987–996CrossRefPubMed

Hermisson M, Klumpp A, Wick W, Wischhusen J, Nagel G, Roos W, Kaina B, Weller M (2006) O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. J Neurochem 96:766–776CrossRefPubMed

Weller M, Thomas DGT (2003) Primary tumors of the central and peripheral nervous system. In: Brandt T, Caplan LR, Dichgans J, Diener HC, Kennard C (eds) Course and treatment of neurological disorders. Academic Press, San Diego, CA, USA, pp 827–863

Demuth T, Berens ME (2004) Molecular mechanisms of glioma cell migration and invasion. J Neurooncol 70:217–228CrossRefPubMed

Gomez GG, Kruse CA (2006) Mechanisms of malignant glioma immune resistance and sources of immunosuppression. Gene Ther Mol Biol 10:133–146PubMed

Koller CA, Miller DM (1986) Preliminary observations on the therapy of the myeloid blast phase of chronic granulocytic leukemia with plicamycin and hydroxyurea. N Engl J Med 315:1433–1438CrossRefPubMed

Yuan P, Wang L, Wei D, Zhang J, Jia Z, Li Q, Le X, Wang H, Yao J, Xie K (2007) Therapeutic inhibition of Sp1 expression in growing tumors by mithramycin A correlates directly with potent antiangiogenic effects on human pancreatic cancer. Cancer 110:2682–2690CrossRefPubMed

Ryuto M, Ono M, Izumi H, Yoshida S, Weich HA, Kohno K, Kuwano M (1996) Induction of vascular endothelial growth factor by tumor necrosis factor alpha in human glioma cells. Possible roles of Sp-1. J Biol Chem 271:28220–28228CrossRefPubMed

Campbell VW, Davin D, Thomas S, Jones D, Roesel J, Tran-Patterson R, Mayfield CA, Rodu B, Miller DM, Hiramoto RA (1994) The G-C specific DNA binding drug, mithramycin, selectively inhibits transcription of the c-myc and c-ha-ras genes in regenerating liver. Am J Med Sci 307:167–172CrossRefPubMed

10.

Lee TJ, Jung EM, Lee JT, Kim S, Park JW, Choi KS, Kwon TK (2006) Mithramycin a sensitizes cancer cells to trail-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites. Mol Cancer Ther 5:2737–2746CrossRefPubMed

11.

Esteve PO, Chin HG, Pradhan S (2007) Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J Biol Chem 282:2615–2625CrossRefPubMed

12.

Rodriguez-Rodero S, Gonzalez S, Rodrigo L, Fernandez-Morera JL, Martinez-Borra J, Lopez-Vazquez A, Lopez-Larrea C (2007) Transcriptional regulation of MICA and MICB: a novel polymorphism in MICB promoter alters transcriptional regulation by Sp1. EurJ Immunol 37:1938–1953CrossRef

13.

Venkataraman GM, Suciu D, Groh V, Boss JM, Spies T (2007) Promoter region architecture and transcriptional regulation of the genes for the MHC class I-related chain A and B ligands of NKG2D. J Immunol 178:961–969PubMed

14.

Koutsodontis G, Kardassis D (2004) Inhibition of p53-mediated transcriptional responses by mithramycin A. Oncogene 23:9190–9200PubMed

15.

Lin RK, Hsu CH, Wang YC (2007) Mithramycin A inhibits DNA methyltransferase and metastasis potential of lung cancer cells. Anti-Cancer Drugs 18:1157–1164CrossRefPubMed

16.

Tagashira M, Kitagawa T, Isonishi S, Okamoto A, Ochiai K, Ohtake Y (2000) Mithramycin represses MDR1 gene expression in vitro, modulating multidrug resistance. Biol Pharmac Bull 23:926–929

17.

Qureshi HY, Sylvester J, El Mabrouk M, Zafarullah M (2005) TGF-beta-induced expression of tissue inhibitor of metalloproteinases-3 gene in chondrocytes is mediated by extracellular signal-regulated kinase pathway and Sp1 transcription factor. J Cell Physiol 203:345–352CrossRefPubMed

18.

Kwak HJ, Park MJ, Cho H, Park CM, Moon SI, Lee HC, Park IC, Kim MS, Rhee CH, Hong SI (2006) Transforming growth factor-beta 1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol Cancer Res 4:209–220CrossRefPubMed

19.

Jungert K, Buck A, Buchholz M, Wagner M, Adler G, Gress TM, Ellenrieder V (2006) Smad-Sp1 complexes mediate TGF-beta-induced early transcription of oncogenic smad7 in pancreatic cancer cells. Carcinogenesis 27:2392–2401CrossRefPubMed

20.

Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC, Van Meir EG (1999) Frequent co-alterations of TP53, p16/CDKN2a, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol 9:469–479CrossRefPubMed

21.

Rensing-Ehl A, Frei K, Flury R, Matiba B, Mariani SM, Weller M, Aebischer P, Krammer PH, Fontana A (1995) Local Fas/Apo-1 (CD95) ligand-mediated tumor cell killing in vivo. Eur J Immunol 25:2253–2258CrossRefPubMed

22.

Naumann U, Huang H, Wolburg H, Wischhusen J, Weit S, Ohgaki H, Weller M (2006) 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 13:469–478CrossRefPubMed

23.

Naumann U, Wischhusen J, Weit S, Rieger J, Wolburg H, Massing U, Weller M (2004) Alkylphosphocholine-induced glioma cell death is BCL-X(L)-sensitive, caspase-independent and characterized by massive cytoplasmic vacuole formation. Cell Death Differ 11:1326–1341CrossRefPubMed

24.

Naumann U, Kügler S, Wolburg H, Wick W, Rascher G, Schulz JB, Conseiller E, Bähr M, Weller M (2001) 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 61:5833–5842PubMed

25.

Naumann U, Schmidt F, Wick W, Frank B, Weit S, Gillissen B, Daniel P, Weller M (2003) Adenoviral natural born killer gene therapy for malignant glioma. Hum Gene Ther 14:1235–1246CrossRefPubMed

26.

Wischhusen J, Melino G, Weller M (2004) p53 and its family members—reporter genes may not see the difference. Cell Death Differ 10:1150–1152CrossRef

27.

Roth W, Isenmann S, Naumann U, Kügler S, Bähr M, Dichgans J, Ashkenazi A, Weller M (1999) Locoregional Apo2l/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun 265:479–483CrossRefPubMed

28.

Weller M, Kleihues P, Dichgans J, Ohgaki H (1998) Cd95 ligand: lethal weapon against malignant glioma? Brain Pathol 8:285-293

29.

Wischhusen J, Naumann U, Ohgaki H, Rastinejad F, Weller M (2003) CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death. Oncogene 22:8233–8245CrossRefPubMed

30.

Kuo L, Chang HC, Leu TH, Maa MC, Hung WC (2006) SRC oncogene activates MMP-2 expression via the ERK/Sp1 pathway. J Cell Physiol 207:729–734CrossRefPubMed

31.

Platten M, Wick W, Weller M (2001) Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 52:401–410CrossRefPubMed

32.

Jennings R, Alsarraj M, Wright KL, Munoz-Antonia T (2001) Regulation of the human transforming growth factor beta type II receptor gene promoter by novel Sp1 sites. Oncogene 20:6899–6909CrossRefPubMed

33.

Li JM, Datto MB, Shen X, Hu PP, Yu Y, Wang XF (1998) Sp1, but not Sp3, functions to mediate promoter activation by TGF-beta through canonical Sp1 binding sites. Nucleic Acids Res 26:2449–2456CrossRefPubMed

34.

Eckerich C, Schulte A, Martens T, Zapf S, Westphal M, Lamszus K (2009) Ron receptor tyrosine kinase in human gliomas: expression, function, and identification of a novel soluble splice variant. J Neurochem 109:969–980CrossRefPubMed

35.

Friese MA, Platten M, Lutz SZ, Naumann U, Aulwurm S, Bischof F, Bühring HJ, Dichgans J, Rammensee HG, Steinle A, Weller M (2003) MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res 63:8996–9006PubMed

36.

Eisele G, Wischhusen J, Mittelbronn M, Meyermann R, Waldhauer I, Steinle A, Weller M, Friese MA (2006) TGFbeta and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 129:2416–2425CrossRefPubMed

37.

Wick W, Platten M, Weller M (2001) Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta. J Neurooncol 53:177–185CrossRefPubMed

38.

Hlobilkova A, Ehrmann J, Knizetova P, Krejci V, Kalita O, Kolar Z (2009) Analysis of VEGF, Flt-1, Flk-1, nestin and MMP-9 in relation to astrocytoma pathogenesis and progression. Neoplasma 56:284–290CrossRefPubMed

39.

Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB, Newcomb EW (2006) Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: Implications for angiogenesis and glioma cell invasion. Lab Invest 86:1221–1232CrossRefPubMed

40.

Rieger L, Weller M, Bornemann A, Schabet M, Dichgans J, Meyermann R (1998) BCL-2 family protein expression in human malignant glioma: a clinical-pathological correlative study. J Neurol Sci 155:68–75CrossRefPubMed

41.

Kleinschmidt-DeMasters BK, Heinz D, McCarthy PJ, Bobak JB, Lillehei KO, Shroyer AL, Shroyer KR (2003) Protein and messenger RNA expression and comparison with telomerase levels. Arch Pathol Lab Med 127:826–833PubMed

42.

Wagenknecht B, Glaser T, Naumann U, Kügler S, Isenmann S, Bähr M, Korneluk R, Liston P, Weller M (1999) Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma. Cell Death Differ 6:370–376CrossRefPubMed

43.

Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R, Mangadu R, Liu YW, Platten M, Herrlinger U, Murphy A, Wong DH, Wick W, Higgins LS, Weller M (2004) SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo. Cancer Res 64:7954–7961CrossRefPubMed

44.

Wick W, Naumann U, Weller M (2006) Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. Curr Pharm Des 12:341–349CrossRefPubMed

45.

Jia Z, Zhang J, Wei D, Wang L, Yuan P, Le X, Li Q, Yao J, Xie K (2007) Molecular basis of the synergistic antiangiogenic activity of bevacizumab and mithramycin A. Cancer Res 67:4878–4885CrossRefPubMed

46.

Wang X, Wang J, Lin S, Geng Y, Wang J, Jiang B (2008) Sp1 is involved in H₂O₂-induced PUMA gene expression and apoptosis in colorectal cancer cells. J Exp Clin Cancer Res 27:44CrossRefPubMed

47.

Lopez-Soto A, Quinones-Lombrana A, Lopez-Arbesu R, Lopez-Larrea C, Gonzalez S (2006) Transcriptional regulation of ULBP1, a human ligand of the NKG2D receptor. J Biol Chem 281:30419–30430CrossRefPubMed

Title: Therapeutic effects of the Sp1 inhibitor mithramycin A in glioblastoma
Authors: Janina Seznec
Björn Silkenstedt
Ulrike Naumann
Publication date: 01-02-2011
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 3/2011
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-010-0266-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Therapeutic effects of the Sp1 inhibitor mithramycin A in glioblastoma

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2011

Convection enhanced delivery of carboplatin in combination with radiotherapy for the treatment of brain tumors

Expression of vascular endothelial growth factor and matrix metalloproteinase-9 in sacral chordoma

High-dose chemotherapy with hematopoietic stem cell transplantation for the treatment of primary central nervous system lymphoma

Endocrinologic, neurologic, and visual morbidity after treatment for craniopharyngioma

Up-front temozolomide in elderly patients with anaplastic oligodendroglioma and oligoastrocytoma

Variable methylation of the imprinted gene, SNRPN, supports a relationship between intracranial germ cell tumours and neural stem cells