Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in adult malignant glioma and various other human solid tumor models but not in normal tissues. To characterize the TRAIL death pathway in childhood primitive neuroectodermal brain tumor (PNET), 8 human PNET cell lines were tested for TRAIL-induced apoptosis. TRAIL-sensitivity of the PNET cell lines was correlated with mRNA expression levels of TRAIL, its agonistic (TRAIL-R1, TRAIL-R2) and antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory protein (cFLIP), caspase-3 and caspase-8. Three of 8 PNET cell lines tested were susceptible to TRAIL-induced apoptosis. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP. However, all TRAIL-sensitive PNET cell lines expressed caspase-8 mRNA and protein, while none of the five TRAIL-resistant PNET cell lines expressed caspase-8 protein. Treatment with the methyltransferase inhibitor 5-aza-2′-deoxycytidine restored mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant PNET cells, suggesting that gene methylation inhibits caspase-8 transcription in these cells. We conclude, that loss of caspase-8 mRNA is an important mechanism of TRAIL-resistance in PNET cells. Treatment with recombinant soluble TRAIL, possibly in combination with methyltransferase inhibitors, represents a promising therapeutic approach for PNET that deserves further investigation.
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References
Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z and Schwall RH. . 1999 J. Clin. Invest. 104: 155–162.
Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P, Blenis J and Tschopp J. . 2000 Nat. Cell Biol. 2: 241–243.
Degli-Esposti MA, Smolak PJ, Walczak H, Waugh J, Huang CP, DuBose RF, Goodwin RG and Smith CA. . 1997 J. Exp. Med. 186: 1165–1170.
Eggert A, Brodeur GM and Ikegaki N. . 2000 Biotechniques 28: 681–691.
Estrov Z, Thall PF, Talpaz M, Estey EH, Kantarjian HM, Andreeff M, Harris D, Van Q, Walterscheid M and Kornblau SM. . 1998 Blood 92: 3090–3097.
Faderl S, Thall PF, Kantarjian HM, Talpaz M, Harris D, Van Q, Beran M, Kornblau SM, Pierce S and Estrov Z. . 1999 Clin. Cancer Res. 5: 4041–4047.
Friesen C, Herr I, Krammer PH and Debatin KM. . 1996 Nat. Med. 2: 574–577.
Fulda S, Sieverts H, Friesen C, Herr I and Debatin KM. . 1997 Cancer Res. 57: 3823–3829.
Gavrieli Y, Sherman Y and Ben-Sasson A. . 1992 J. Cell Biol. 119: 493–501.
Grenet J, Teitz T, Wei T, Valentine V and Kidd KJ. . 1999 Gene 226: 225–232.
Griffith TS, Chin WA, Jackson GC, Lynch DH and Kubin MZ. . 1998b J. Immunol. 161: 2833–2840.
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE and Tschopp J. . 1997 Nature 388: 190–195.
Juo P, Kuo CJ, Yuan J and Blenis J. . 1998 Curr. Biol. 8: 1001–1008.
Mariani SM, Matiba B, Armandola EA and Krammer PH. . 1997 J. Cell Biol. 137: 221–229.
Marsters SA, Pitti RM, Donahue CJ, Ruppert S, Bauer KD and Ashkenazi A. . 1996 Curr. Biol. 6: 750–752.
Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, Yuan J, Gurney A, Goddard AD, Godowski P and Ashkenazi A. . 1997 Curr. Biol. 7: 1003–1006.
Marsters SA, Pitti RA, Sheridan JP and Ashkenazi A. . 1999 Recent. Prog. Horm. Res. 54: 225–234.
Mosmann T. . 1983 J. Immunol. Methods 65: 55–63.
Nagata S. . 1997 Cell 88: 355–365.
Nakamura M, Rieger J, Weller M, Kim J, Kleihues P and Ohgaki H. . 2000 Acta Neuropathol. 99: 1–6.
Packer RJ, Sutton LN, Elterman R, Lange B, Goldwein J, Nicholson SH, Mulne L, Boyett J, D'Angio GJ, Wechsler-Jentzsch K, Reaman G, Cohen BH, Bruce DA, Rorke LB, Molloy P, Ryan J, LaFond D, Evans AE and Schut L. . 1994 J. Neurosurg. 81: 690–698.
Pan G, O'Rourke K, Chinnaiyen AM, Gentz R, Ebner R, Ni J and Dixit VM. . 1997a Science 276: 111–113.
Pan G, Ni J, Wei YF, Yu GI, Gentz R and Dixit VM. . 1997b Science 277: 815–818.
Pan G, Ni J, Yu G, Wei YF and Dixit VM. . 1998 FEBS Lett. 424: 41–45.
Phillips TA, Ni J, Pan G, Ruben SM, Wei YF, Pace JL and Hunt JS. . 1999 J. Immunol. 162: 6053–6059.
Pollack IF. . 1994 N. Engl. J. Med. 331: 1500–1507.
Rieger J, Naumann U, Glaser T, Ashkenazi A and Weller M. . 1998 FEBS Lett. 427: 124–128.
Russo C, Pellarin M, Tingby O, Bollon AW, Lamborn KR, Mohapatra G, Collins VP and Feuerstein BG. . 1999 Cancer 86: 331–339.
Schulze-Osthoff K, Ferrari D, Los M, Wesselborg S and Peter ME. . 1998 Eur. J. Biochem. 254: 439–459.
Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P and Ashenkenazi A. . 1997 Science 277: 818–821.
Tang XX, Evans AE, Zhao H, Cnaan A, London W, Cohn SL, Brodeur GM and Ikegaki N. . 1999 Clin. Cancer Res. 5: 1491–1496.
Thomas WD and Hersey P. . 1998 J. Immunol. 161: 2195–2200.
Tschopp J, Irmler M and Thome M. . 1998 Curr. Opin. Immunol. 10: 552–558.
Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P and Wallach D. . 1998 Immunity 9: 267–276.
Vassalli P. . 1992 Annu. Rev. Immunol. 10: 411–452.
Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG and Rauch CT. . 1997 EMBO J. 16: 5386–5397.
Weller M, Schuster M, Pietsch T and Schabet M. . 1998 Cancer Lett. 128: 121–126.
Wu GS, Burns TF, McDonald III ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G and El-Deiry WS. . 1997 Nature Genetics 17: 141–143.
Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA and Goodwin RG. . 1995 Immunity 3: 673–682.
Zhang XD, Franco A, Myers K, Gray C, Nguyen T and Hersey P. . 1999 Cancer Res. 59: 2747–2753.
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Supported from the Jeffrey Miller Neuro-Oncology Research Fund (MA Grotzer.)
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Grotzer, M., Eggert, A., Zuzak, T. et al. Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 19, 4604–4610 (2000). https://doi.org/10.1038/sj.onc.1203816
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DOI: https://doi.org/10.1038/sj.onc.1203816
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