Synthesis and biological effects of NO in malignant glioma cells: modulation by cytokines including CD95L and TGF-beta, dexamethasone, and p53 gene transfer.
Rieger, Johannes; Ständer, Marko; Löschmann, Peter A.et al.
[en] Nitric oxide (NO) is thought to play an important role in neurotransmission, inflammation, and regulation of cell death in the mammalian brain. Here, we examined the synthesis and biological effects of NO in human malignant glioma cells. Exposure to cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and lipopolysaccharide (LPS) induced NO synthesis in rat C6 and A172 human glioma cells, but not in LN-229, T98G or LN-18 human malignant glioma cells. Induced release of NO involved enhanced expression of inducible NO synthase (iNOS). Failure to detect NO release in the latter cell lines was not overcome by neutralization of endogenous TGF-beta or by coexposure to cytokines, LPS, and antioxidants. Apoptosis induced by CD95 ligand (CD95L) did not involve NO formation. Neither NOS inhibitors nor NO donators modulated CD95L-induced apoptosis. Dexamethasone (DEX)-mediated protection of glioma cells from CD95L-induced apoptosis was also independent of DEX effects on NO metabolism. DEX inhibited not only cytokine/LPS-evoked NO release but also attenuated the toxicity of NO in three of five cell lines. Forced expression of temperature-sensitive p53 val135 in C6 cells in either mutant or wild-type conformation inhibited cytokine/LPS-induced NO synthesis. Further, accumulation of p53 in both mutant or wild-type conformation protected glioma cells from the toxicity of exogenous NO, consistent with a gain of p53 function associated with p53 accumulation. We conclude that resistance to NO-dependent immune defense mechanisms may contribute to the malignant progression of human cancers with p53 alterations, notably those associated with the accumulation of mutant p53 protein.
Disciplines :
Oncology
Author, co-author :
Rieger, Johannes; Department of Neurology, University of Tübingen, School of Medicine, Germany
Ständer, Marko; Lab. of Molecular Neuro-Oncology, University of Tübingen, School of Medicine, Tübingen, Germany
Löschmann, Peter A.; Laboratory of Neuropharmacology, University of Tübingen, School of Medicine, Tübingen, Germany
HENEKA, Michael ; Laboratory of Neuropharmacology, University of Tübingen, School of Medicine, Tübingen, Germany
Dichgans, Johannes; Laboratory of Neuropharmacology, University of Tübingen, School of Medicine, Tübingen, Germany
Klockgether, Thomas; Laboratory of Neuropharmacology, University of Tübingen, School of Medicine, Tübingen, Germany
Weller, Michael; Lab. of Molecular Neuro-Oncology, University of Tübingen, School of Medicine, Tübingen, Germany
External co-authors :
yes
Language :
English
Title :
Synthesis and biological effects of NO in malignant glioma cells: modulation by cytokines including CD95L and TGF-beta, dexamethasone, and p53 gene transfer.
Albina JE, Cui S, Mateo RB and Reichner JS. (1993). J. Immunol., 150, 5080-5085.
Asai A, Miyagi Y, Sugiyama A, Gamanuma M, Hong SI, Takamoto S, Nomura K, Matsutani M, Takakura K and Kuchino Y. (1994). J. Neuro-Oncol., 19, 259-268.
Bernatowicz A, Koedel U, Frei K, Fontana A and Pfister H-W. (1995). J. Neuroimmunol., 60, 53-61.
Blanco FJ, Ochs RL, Schwarz H and Lotz M. (1995). Am. J. Pathol., 146, 75-85.
Caelles C, Helmberg A and Karin M. (1994). Nature, 370, 220-223.
Calmels S, Hainaut P and Ohshima H. (1997). Cancer Res., 57, 3365-3369.
Cobbs CS, Brenman JE, Aldape KD, Bredt DS and Israel MA. (1995). Cancer Res., 55, 727-730.
Dimmeler S, Haendeler J, Nehls M and Zeiher AM. (1997). J. Exp. Med., 185, 601-607.
Ellie E, Loiseau H, Lafond F, Arsaut J and Demotes-Mainard J. (1995). Neuroreport, 7, 294-296.
Ewen ME, Oliver CJ, Sluss HK, Miller SJ and Peeper DS. (1995). Genes Dev., 9, 204-217.
Fehsei K, Kroencke K-D, Meyer KL, Huber H, Wahn V and Kolb-Bachofen V. (1995). J. Immunol., 155, 2858-2865.
Feinstein DL, Galea E, Roberts S, Berquist H, Wang H and Reis DJ. (1994). J. Neurochem., 62, 315-321.
Forrester K, Ambs S, Lupold SE, Kapust RB, Spillare EA, Weinberg WC, Felley-Bosco E, Wang XW, Geller DA, Tzeng E, Billiar TR and Harris CC. (1996). Proc. Natl. Acad. Sci. USA, 93, 2442-2447.
Fujisawa H, Ogura T, Hokari A, Weisz A, Yamashita J and Esumi H. (1995). J. Neurochem., 64, 85-91.
Fukuo K, Hata S, Sahara T, Nakahashi T, Shinto Y, Tsujimoto Y, Morimoto S and Ogihara T. (1996). Hypertension, 27, 823-826.
Harvey M, Vogel H, Morris D, Bradley A, Bernstein A and Donehower DA. (1995). Nature Genetics, 9, 305-311.
Haupt Y, Rowan S, Shaulian E, Vousden HK and Oren M. (1995). Genes Dev., 9, 2170-2183.
Ho Y-S, Wang Y-J and Lin J-K. (1996). Mol. Carcinog., 16, 20-31.
Horikoshi N, Usheva A, Chen J, Levine AJ, Weinmann R and Shenk T. (1995). Mol. Cell. Biol., 15, 227-234.
Kawase M, Kinouchi H, Kato I, Akabane A, Kondo T, Arai S, Fujimura M, Okamoto H and Yoshimoto T. (1996). Brain Res., 738, 319-322.
Kilbourn R and Belloni I. (1990). J. Natl. Cancer Inst., 82, 772-776.
Levine AJ. (1997). Cell, 88, 323-331.
Liu X, Miller C, Koeffler P and Berk A. (1993). Mol. Cell. Biol., 13, 3291-3300.
Marietta M, Yoon P, Iyengar R, Leaf C and Wishnok J. (1988). Biochemistry, 27, 8706-8711.
Messmer UK, Ankarcrona M, Nicotera P and Brüne B. (1994). FEBS Lett., 355, 23-26.
Michalowitz D, Halevy O and Oren M. (1990). Cell, 62, 671-680.
Murata J, Corradin SB, Felley-Bosco E and Juillerat-Jeanneret L. (1995). Int. J. Cancer, 62, 743-748.
Murphy S, Simmons ML, Agullo L, Garcia A, Feinstein DL, Galea E, Reis DJ, Minc-Golomb D and Schwartz JP. (1993). Trends Neurosci., 16, 323-328.
Radomski MW, Palmer RMJ and Moncada S. (1990). Proc. Natl. Acad. Sci. USA, 87, 10043-10047.
Rensing-Ehl A, Frei K, Flury R, Matiba B, Mariani SM, Weller M, Aebischer P, Krammer PH and Fontana A. (1995). Eur. J. Immunol., 25, 2253-2258.
Roth W, Fontana A, Trepel M, Dichgans J, Reed JC and Weller M. (1997). Cancer Immunol. Immunother., 44, 55-63.
Ryan JJ, Prochownik F, Gottlieb CA, Apel IJ, Merino R, Nunez G and Clarke MF. (1994). Proc. Natl. Acad. Sci. USA, 91, 5878-5882.
Seto F, Usheva A, Zambetti GP, Momand J, Horikoshi N, Weinmann R, Levine AJ and Shenk T. (1992). Proc. Natl. Acad. Sci. USA, 89, 12028-12032.
Siminons ML and Murphy S. (1992). J. Neurochem., 59, 897-905.
Simmons ML and Murphy S. (1993). Eur. J. Neurosci., 5, 825-831.
Stuehr DJ and Nathan CF. (1989). J. Exp. Med., 169, 1543-1555.
Trepel M, Dichgans J, Malipiero U, Fontana A and Weller M. (1996). J. Neuro-Oncol., 30, 95.
Trepel M, Scheding S, Groscurth P, Horny H-P, Malipiero U, Brugger W, Dichgans J and Weller M. (1997). Leukemia, in press.
Van Meir EG, Kikuchi T, Tada T, Li H, Diserens AC, Wojcik BE, Huang HJS, Friedmann T, DeTribolet N and Cavenee WK. (1994). Cancer Res., 54, 649-652.
Vigne P, Damais C and Frelin C. (1993). Brain Res., 606, 332-334.
Vodovotz Y, Bogdan C, Paik J, Xie Q and Nathan C. (1993). J. Exp. Med., 178, 605-613.
Wagenknecht B, Gulbins F, Lang F, Dichgans J and Weller M. (1997a). FEBS Lett., 409, 17-23.
Wagenknecht B, Trepel M, Von Deimling A, Grimmel C, Rollbrocker B, Hayashi Y, Lang F, Dichgans J, Gulbins E and Weller M. (1997b). Cell. Physiol. Biochem., 19, 459-470.
Weller M and Fontana A. (1995). Brain. Res. Brain. Res. Rev., 21, 128-151.
Weller M, Frei K, Groscurth P, Krammer PH, Yonekawa Y and Fontana A. (1994). J. Clin. Invest., 94, 954-964.
Weller M, Malipiero U, Aguzzi A, Reed JC and Fontana A. (1995a). J. Clin. Invest., 95, 2633-2643.
Weller M, Malipiero U, Rensing-Ehl A, Barr PJ and Fontana A. (1995b). Cancer Res., 55, 2936-2944.
Weller M, Schmidt C, Roth W and Dichgans J. (1997a). Neurology, 48, 1704-1709.
Weller M, Trepel M, Grimmel C, Schabet M, Bremen D, Krajewski S, Reed JC. (1997b). Neurol. Res., 19, 459-470.
Weller M, Winter S, Schmidt C, Esser P, Fontana A, Dichgans J and Groscurth P. (1997c). Int. J. Cancer, 73, 707-714.
Wu C-C, Croxtall JD, Perretti M, Bryant CF, Thiemermann C, Flower RJ and Vane JR. (1995). Proc. Natl. Acad. Sci. USA, 92, 3473-3477.
Yonehara S, Ishii A and Yonehara M. (1989). J. Exp. Med., 169, 1747-1756.
