Abstract
We studied the expression of antioxidant enzymes (AOEs) and related proteins manganese superoxide dismutase (MnSOD), thioredoxin (Trx), thioredoxin reductase (TrxR), and the catalytic (GLCL‐c) and regulatory (GLCL‐r) subunits of glutamate cysteine ligase (γ‐glutamylcysteinesynthetase) in 433 astrocytomas. Expression of MnSOD was found in 91%, Trx in 46%, TrxR in 66%, GLCL‐c 73% and GLCL‐r in 89% of the cases. Diffuse astro‐cytomas showed more intense staining for Trx (p= 0.002), TrxR (p=0.004), GLCL‐c (p=0.001), GLCL‐r (p=0.04) and MnSOD (p=0.01) than pilocytic astrocytomas. Within diffuse astrocytomas only Trx (p= 0.0001) and TrxR (p=0.04) significantly associated with increased malignancy grade. Necrotic tumors were more often immunopositive for Trx (p=0.001) and TrxR (p=0.02) and AOE expression was generally higher in mitotically active tumors. Expression of Trx and lack of MnSOD expression was associated with a worse prognosis in diffuse astrocytomas. None of the AOEs had any prognostic value in pilocytic grade I astrocytomas. Familial astrocytomas, which included 23 of the cases studied, did not differ in their expression of MnSOD from sporadic ones. The results show that MnSOD and Trx may influence the biological behaviour of astrocytomas, possibly by modulating cell proliferation and necrosis in these tumors.
Full Text
The Full Text of this article is available as a PDF (356.6 KB).
References
- 1. Carlsson LM, Johsson J, Edlund T, Marklund SL (1995) Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Acad Natl Sci U S A 92:6264–6268. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Cecchi C, Latorraca S, Sorbi S, Iantomasi T, Favilli F, Vincenzini MT, Liguri G (1999) Glutathione level is altered in lymphoblasts from patients with familial Alzheimer's Neurosci Lett 275:152–154. [DOI] [PubMed] [Google Scholar]
- 3. Church SL, Grant JW, Meese EU, Trent JM (1992) Sublocalization of the gene encoding manganese superoxide dis‐mutase (MnSOD/SOD2) to 6q25 by fluorescence in situ hybridization and somatic cell hybrid mapping. Genomics 14:823–825. [DOI] [PubMed] [Google Scholar]
- 4. Cobbs CS, Levi DS, Aldape K, Israel MA (1996) Manganese superoxidase dismutase expression in human central nervous system tumors. Cancer Res 56:3192–3195. [PubMed] [Google Scholar]
- 5. Crapo JD, Oury TD, Rabouille C, Slot JW, Chang LY (1992) Copper zinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc Natl Acad Sci U S A 89:10405–10409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Dalton TP, Dieter MZ, Yang Y, Shertzer HG, Nebert DW (2000) the most glutamate cysteine ligase catalytic subunit (Gclc) gene: embryonic lethal when homozygous, and proposed model for moderate glutathione deficiency when heterzygous. Biochem Biophys Res Commun 20:279. [DOI] [PubMed] [Google Scholar]
- 7. Das K, Lewis‐Molock Y, White CW (1995) Activation of NK‐kB and elevation of MnSOD gene expression by thiol reducing agents in lung adenocarcinoma (A549) cells. Am J Physiol 269; L688–L602. [DOI] [PubMed] [Google Scholar]
- 8. Folz RJ, Crapo JD (1994) Extracellular superoxide dismutase (SOD3): Tissue‐specific expression, genomic characterization, and computer assisted sequence analysis of the human EcSOD gene. Genomics 22:162–171. [DOI] [PubMed] [Google Scholar]
- 9. Grogan TM, Fenoglio‐Prieser C, Zeheb R, Bellamy W, Frutiger Y, Vela E, Stemmerman G, MacDonald J, Richter L, Gallegos A, Powis G (2000) Thioredoxin, a putative oncogene product is overexpressed in gastric carcinoma and associated with increased proliferation and increased cell survival. Hum Pathol 31:475–481. [DOI] [PubMed] [Google Scholar]
- 10. Haapasalo H, Hyytinen E, Sallinen P, Helin H, Kallioniemi OP, Isola J (1996) c‐erbB‐2 oncogene in astrocytic neoplasms: infrequent overexpression by immuno‐histo‐chemistry and absence of gene amplification by FISH. Br J Cancer 73:620–623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Halliwell B (1991) Reactive oxygen species in living systems: source, biochemistry and role in human disease. Am J Med 91:14S–22S. [DOI] [PubMed] [Google Scholar]
- 12. Janssen AM, Bosman CB, van Duijn W, Oostendorp‐van de Ruit MM, Kubben FJ, Griffioen G, Lamers CB, van Krieken JH, van de Velde CJ, Verspaget HW (2000) Superoxide dismutases in gastric and esophageal cancer and the prognostic impact in gastric cancer. Clin Cancer Res 6:3183–3192. [PubMed] [Google Scholar]
- 13. Hanigan MH, Frierson HF Jr, Swanson PE, De Young BR (1999) Altered expression of gamma‐glutamyl transpep‐tidase in human tumors. Hum Pathol 30:300–305. [DOI] [PubMed] [Google Scholar]
- 14. Holmgren A (1989) Thioredoxin and glutaredoxin systems. J Biol Chem 264:13963–13966. [PubMed] [Google Scholar]
- 15. Holmgren A, Björnstedt M (1995) Thioredoxin and thioredoxin reductase. Methods Enzymol 252:199–208. [DOI] [PubMed] [Google Scholar]
- 16. Kahlos K, Pääkkö P, Kurttila E, Soini Y, Kinnula V (2000) Manganese superoxide dismutase as a diagnostic and prognostic marker for malignant pleural mesothelioma. Br J Cancer 82:1022–1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Kimura M, Kapas L, Krueger JM (1998) Oxidized glutathione promotes sleep in rabbits. Brain Res Bull 45:545–548. [DOI] [PubMed] [Google Scholar]
- 18. Kinnula VL, Crapo JD, Raivio KO (1995) Generation and disposal of reactive oxygen metabolites in the lung. Lab Invest 73:3–19. [PubMed] [Google Scholar]
- 19. Kleinhues P, Cavenee WK (eds.) (2000) Pathology and genetics of tumors of the nervous system. WHO Classification of Tumors. IARC Press. Lyon , France . [Google Scholar]
- 20. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP (1998) Tissue microarrays for highthroughput molecular profiling of tumor specimens. Nat Med 4:844–847. [DOI] [PubMed] [Google Scholar]
- 21. Li Y, Huang T‐T, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ (1995) Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dis‐mutase. Nat Gen 11:376–381. [DOI] [PubMed] [Google Scholar]
- 22. Li J‐J, Oberley LW, St , Clair DK, Ridnour LA, Oberley TD (1995) Phenotypic Changes induced in human breast cancer cells by overexpression of manganese‐containing superoxide dismutase. Oncogene 10:1989–2000. [PubMed] [Google Scholar]
- 23. Li J‐J, Oberley LW, Fan M, Colburn NH (1998) Inhibition of AP‐1 and NF‐kB by manganese‐containing superoxide dismutase in human breast cancer cells. FASEB J 12:1713–1723. [DOI] [PubMed] [Google Scholar]
- 24. Li J‐J, Colburn NH, Oberley LW (1998) Maspin gene expression in tumor suppression induced by overexpressing manganese‐containing superoxide dismutase cDNA in human breast cancer cells. Carcinogenesis 19:833–839. [DOI] [PubMed] [Google Scholar]
- 25. Manna SK, Zhang HJ, Yan T, Oberley LW, Aggarwal BB (1998) Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor‐induced apoptosis and activation of nuclear transcription factor‐kB and activated protein‐1. J Biol Chem 273:13245–13254. [DOI] [PubMed] [Google Scholar]
- 26. Marklund SL, Westman NG, Lundgren E, Roos G (1982) Copper‐ and zinc‐containing superoxide dismutase, manganese‐containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues. Cancer Res 42:1955–1961. [PubMed] [Google Scholar]
- 27. Mustacich D, Powis G (2000) Thioredoxin reductase. Biochem. J 346:1–8. [PMC free article] [PubMed] [Google Scholar]
- 28. Nakamura M, Watanabe T, Klangby U, Asker C, Winman K, Yonekawa Y, Kleinhues P, Ohgaki (1996) Glutathione and related enzymes in multidrug resistance. Eur J Cancer. 32A:967–978. [DOI] [PubMed] [Google Scholar]
- 29. Nishida S, Akai F, Iwasaki H, Hosokawa K, Kusunoki T, Suzuki K, Taniguchi N, Hashimoto S, Tamura TT (1993) Manganese superoxide dismutase content and localization in human thyroid tumors. J Pathol 169:341–345. [DOI] [PubMed] [Google Scholar]
- 30. Oury TD, Day BJ, Crapo DJ (1996) Extracellular superoxide dismutase: a regulator of nitric oxide bioavailability. Lab Invest 75:617–636. [PubMed] [Google Scholar]
- 31. Paunu N, Pukkala E, Laippala P, Sankila R, Isola J, Miettinen H, Simola K, Helén P, Helin H, Haapasalo H (2002) Cancer incidence in families with multiple glioma patients. Int J Cancer 97:819–822. [DOI] [PubMed] [Google Scholar]
- 32. Paunu N, Sallinen S‐L, Karhu R, Miettinen H, Sallinen P, Kononen J, Laippala P, Simola K, Helén P, Haapasalo H (2000) Chromosome imbalances in familial gliomas detected by comparative genomic hybridization. Gen Chromos Cancer 29:339–346. [DOI] [PubMed] [Google Scholar]
- 33. Powis G, Oblong JE, Gasdaska PY, Berggren M, Hill SR, Kirkpatrick DL (1994) The thioredoxin/thioredoxin reductase redox system and control of cell growth. Oncol Res 6:539–544. [PubMed] [Google Scholar]
- 34. Powis G, Kirkpatrick DL, Angulo M, Baker A (1998). Thioredoxin redox control of cell growth and death and the effects of inhibitors. Chem Biol Interact 111–112:23–24. [DOI] [PubMed] [Google Scholar]
- 35. Ranganathan AC, Nelson KK, Rodriguez AM, Kim KH, Tower GB, Rutter JL, Brinckerhoff CE, Huang TT, Epstein CJ, Jeffrey JJ, Melendez JA (2001) Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2‐dependent ERK1/2 activation. J Biol Chem 276:14264–14270. [DOI] [PubMed] [Google Scholar]
- 36. Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood DG, Beal MF, Brown RH Jr, Scott RW, Snider WD (1996) Motor neurons in Cu/Zn superoxide dismutase‐deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13:43–47. [DOI] [PubMed] [Google Scholar]
- 37. Sallinen P, Haapasalo H, Visakorpi T, Helen P, Rantala I, Isola J, Helin H (1994) Relation of Ki‐67 (MIB‐1), PCNA and S‐phase fraction with patient survival in formalinfixed, paraffin‐ embedded astrocytoma material. J Pathol 174:275–282. [DOI] [PubMed] [Google Scholar]
- 38. Sasada T, Iwata S, Sato N, Kitaoka Y, Hirota K, Nakamu‐ra K, Nishiyama A, Taniguchi Y, Takabayashi A, Yodoi J (1996) Redox control of resistance to cisdiamminedichloroplatinum (II) (CDDP): protective effect of human thioredoxin against CDDP‐induced cytotoxicity. J Clin Invest 97:2268–2276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Sasada T, Nakamura H, Ueda S, Sato N, Kitaoka Y, Gon Y, Takabayashi A, Spyrou G, Holmgren A, Yodoi J (1999) Possible involvement of thioredoxin reductase as well as thioredoxin in cellular sensitivity to cis‐diamminedichloroplatinum. Free Radic Biol Med 27:504–514. [DOI] [PubMed] [Google Scholar]
- 40. Seeling GF, Simondsen RP, Meister A (1984) Reversible dissociation of gGCS into 2 subunits. J Biol Chem 259:9345–9347. [PubMed] [Google Scholar]
- 41. Soini Y, Kahlos K, Näpänkangas U, Kaarteenaho‐Wiik R, Säily M, Koistinen P, Pääkkö P, Holmgren A, Kinnula VL (2001) Widespread expression of thioredoxin and thioredoxin reductase in non‐small cell lung carcinoma. Clin Cancer Res 7:1750–1757. [PubMed] [Google Scholar]
- 42. Soini Y, Vakkala M, Kahlos K, Pääkkö P, Kinnula V (2001). MnSOD expression is less frequent in tumor cells of invasive breast carcinomas than in situ carcinomas or non‐neoplastic breast epithelial cells. J Pathol 195:156–162. [DOI] [PubMed] [Google Scholar]
- 43. Sun QA, Wu Y, Zappacosta F, Jeang KT, Lee BJ, Hatfield DL, Gladyshev VN (1999) Redox regulation of cell sig‐nalling by selenocysteine in mammalian thioredoxin reductases. J Biol Chem 274:24522–24530. [DOI] [PubMed] [Google Scholar]
- 44. Tew KD (1994) Glutathione‐associated enzymes in anticancer drug resistance. Cancer Res 54:4313–4320. [PubMed] [Google Scholar]
- 45. Toh Y, Kuninaka S, Oshiro T, Ikeda Y, Nakashima H, Baba H, Kohnoe S, Okamura T, Mori M, Sugimachi K (2000) Overexpression of manganese superoxide dis‐mutase mRNA may correlate with aggressiveness in gastric and colorectal adenocarcinomas. Int J Oncol 17:107–112. [DOI] [PubMed] [Google Scholar]
- 46. Yantiri F, Gasparayan A, Andersen JK (2001) Glutamyl cysteine synthetase catalytic and regulatory subunits localize to dopaminergic nigral neurons as well as to astrocytes. J Neurosci Res 64:203–206. [DOI] [PubMed] [Google Scholar]
- 47. Yokomizo A, Ono M, Nanri H, Makino Y, Ohga T, Wada M, Okamoto T, Yodoi J, Kuwano M, Kohno K (1995) Cellular levels of thioredoxin associated with drug sensitivity to cisplatin, mitomycin C, doxorubicin, and etoposide. Cancer Res 55:4293–4296. [PubMed] [Google Scholar]
- 48. Zhang K, Mack P, Wong KP (1998) Glutathione‐related mechanisms in cellular resistance to anticancer drugs. Int J Oncol 12:871–882. [DOI] [PubMed] [Google Scholar]
- 49. Zhang K, Yang EB, Wong KP, Mack P (1999) GSH, GSH‐related enzymes and GS‐X pump in relation to sensitivity of human tumor cell lines to chlorambucil and adriamycin. Int J Oncol. 14:861–867. [DOI] [PubMed] [Google Scholar]
- 50. Zhao Y, Xue Y, Oberley TD, Kiningham KK, Lin S‐M, Yen H‐C, Majima H, Hines J, St. Clair D (2001) Overexpression of manganese superoxide dismutase supresses tumor formation by modulation of activator protein‐1 signaling in a multistage skin carcinogenesis model. Cancer Res 61:6082–6088. [PubMed] [Google Scholar]
- 51. Zhong L, Arner ES, Holmgren A (2000) Structure and mechanism of human thioredoxin reductase: the active site is a redox‐active selenolthiol/selenenylsulfide formed from the conserved cysteine‐selenocysteine sequence. Proc Natl Acad Sci U S A 97:5854–5859. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. Zhong W, Oberley LW, Oberley TD, Clair DKS (1997) Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase. Oncogene 14:481–490. [DOI] [PubMed] [Google Scholar]