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Tumor Biology |
Neuro-Oncology Program, Department of Oncology, University Children's Hospital Zürich, 8032 Zürich, Switzerland
3 Send correspondence to Michael Grotzer, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland (Michael.Grotzer{at}kispi.unizh.ch).
Abstract
Primitive neuroectodermal tumors (PNETs), including medulloblastoma
(PNET/MB) and supratentorial PNET (sPNET), are the most common malignant brain
tumors of childhood. The stabilization of telomere lengths by telomerase
activation is an important step in carcinogenesis and cell immortalization.
Epigallocatechin gallate (EGCG), the major polyphenol in green tea, is a
telomerase inhibitor with antiproliferative and anticarcinogenic effects
against different types of cancer. In this study, we used real-time reverse
transcriptase-polymerase chain reaction to measure the mRNA expression of the
human telomerase reverse transcriptase (hTERT) in 50 primary PNET samples (43
PNET/MB, 7 sPNET), 14 normal human brain samples, and 6 human PNET cell lines.
Compared to normal human cerebellum, 38/50 (76%) primary PNET samples had
5-fold upregulated hTERT mRNA expression. We then examined PNET cell lines
for telomerase activity using a quantitative telomeric repeat amplification
protocol (TRAP), and for telomere length using terminal restriction fragment
analysis. While a positive correlation between hTERT mRNA expression and
telomerase activity was detected in PNET cell lines, no correlation was found
between telomerase activity and telomere length. Treatment of PNET cell lines
with EGCG resulted in a dose-dependent inhibition of telomerase activity at
micromolar levels. Although EGCG displayed strong proliferation inhibitory
effects against TRAP-positive PNET cell lines, it had no significant effect
against TRAP-negative D425 cells. These results provide evidence for a
possible role of telomerase in the pathogenesis of most PNETs and indicate
that subsets of PNETs maintain telomere length by alternative mechanisms.
Inhibition of telomerase function represents a novel experimental therapeutic
strategy in childhood PNETs that warrants further investigation.
References
Bieche, I., Nogues, C., Paradis, V., Olivi, M., Bedossa, P.,
Lidereau, R., and Vidaud, M. (2000) Quantitation of hTERT gene
expression in sporadic breast tumors with a real-time reverse
transcription-polymerase chain reaction assay. Clin. Cancer
Res. 6,452
-459.
Blackburn, E.H. (1991) Structure and function of telomeres. Nature 350,569 -573.[CrossRef][Medline]
Bosoy, D., Peng, Y., Mian, I.S., and Lue, N.F. (2003)
Conserved N-terminal motifs of telomerase reverse transcriptase required for
ribonucleoprotein assembly in vivo. J. Biol. Chem.
278,3882
-3890.
Bryan, T.M., and Cech, T.R. (1999) Telomerase and the maintenance of chromosome ends. Curr. Opin. Cell Biol. 11,318 -324.[CrossRef][Web of Science][Medline]
Bryan, T.M., Englezou, A., Gupta, J., Bacchetti, S., and Reddel, R.R. (1995) Telomere elongation in immortal human cells without detectable telomerase activity. Embo J. 14,4240 -4248.[Web of Science][Medline]
Bustin, S.A. (2000) Absolute quantification of mRNA using real-time reverse tran scription polymerase chain reaction assays. J. Mol. Endocrinol. 25,169 -193.[Abstract]
Cao, Y., and Cao, R. (1999) Angiogenesis inhibited by drinking tea. Nature 398, 381.[CrossRef][Medline]
DeMasters, B.K., Markham, N., Lillehei, K.O., and Shroyer, K.R. (1997) Differential telomerase expression in human primary intracranial tumors. Am. J. Clin. Pathol. 107,548 -554.[Web of Science][Medline]
Falchetti, M.L., Larocca, L.M., and Pallini, R. (2002) Telomerase in brain tumors. Childs Nerv. Syst. 18,112 -117.[CrossRef][Web of Science][Medline]
Feng, J., Funk, W.D., Wang, S.-S., Weinrich, S.L., Avilion, A.A.,
Chiu, C.-P., Adams, R.R., Chang, E., Allsopp, R.C., Yu, J., Le, S., West,
M.D., Harley, C.B., Andrews, W.H., Greider, C.W., and Villeponteau, B.
(1995) The RNA component of human telomerase.
Science 269,1236
-1241.
Folini, M., Colella, G., Villa, R., Lualdi, S., Daidone, M.G., and Zaffaroni, N. (2000) Inhibition of telomerase activity by a hammerhead ribozyme tar geting the RNA component of telomerase in human melanoma cells. J. Invest. Dermatol. 114,259 -267.[CrossRef][Web of Science][Medline]
Fujiki, H., Suganuma, M., Okabe, S., Sueoka, E., Sueoka, N., Fujimoto, N., Goto, Y., Matsuyama, S., Imai, K., and Nakachi, K. (2001) Cancer prevention with green tea and monitoring by a new biomarker, hnRNP B1. Mutat. Res. 480-481,299 -304.
Fujiki, H., Suganuma, M., Okabe, S., Sueoka, E., Suga, K., Imai, K., Nakachi, K., and Kimura, S. (1999) Mechanistic findings of green tea as cancer preventive for humans. Proc. Soc. Exp. Biol. Med. 220,225 -228.[CrossRef][Medline]
Giulietti, A., Overbergh, L., Valckx, D., Decallonne, B., Bouillon, R., and Mathieu, C. (2001) An overview of real-time quantitative PCR: Applications to quantify cytokine gene expression. Methods 25,386 -401.[CrossRef][Web of Science][Medline]
Grosso, R., and Schiffer, D. (1998) Prognostic significance of telomerase in brain tumors. Crit. Rev. Neurosurg. 8,244 -247.
Grotzer, M.A., Eggert, A., Zuzak, T.J., Janss, A.J., Marwaha, S., Wiewrodt, B.R., Ikegaki, N., Brodeur, G.M., and Phillips, P.C. (2000) Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression. Oncogene 19,4604 -4610.[CrossRef][Web of Science][Medline]
Grotzer, M.A., Hogarty, M.D., Janss, A.J., Liu, X., Zhao, H.,
Eggert, A., Sut ton, L.N., Rorke, L.B., Brodeur, G.M., and Phillips, P.C.
(2001) MYC messenger RNA expression predicts survival outcome in
childhood primitive neuroectodermal tumor/medulloblastoma. Clin.
Cancer Res. 7,2425
-2433.
Gurney, J.G., Smith, M.A., and Bunin, G.R. (1999) CNS and miscellaneous intracranial and intraspinal neoplasms. In: Ries, L.A.G., Smith, M.A., Gurney, J.G., Linet, M., Tamra, T., Young, J.L. and Bunin, G.R. (Eds.), Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649. Bethesda, Md.: National Insti tutes of Health.
Hanahan, D., and Weinberg, R.A. (2000) The hallmarks of cancer. Cell 100,57 -70.[CrossRef][Web of Science][Medline]
Harrison, R.J., Gowan, S.M., Kelland, L.R., and Neidle, S. (1999) Human telomerase inhibition by substituted acridine derivatives. Bioorg. Med. Chem. Lett. 9,2463 -2468.[CrossRef][Medline]
Hasaniya, N., Youn, K., Xu, M., Hernaez, J., and Dashwood, R. (1997) Inhibitory activity of green and black tea in a free radical-generating system using 2-amino-3-methylimidazo[4,5-f]quinoline as substrate. Jpn. J. Cancer Res. 88,553 -558.[CrossRef][Web of Science][Medline]
Hayakawa, N., Nozawa, K., Ogawa, A., Kato, N., Yoshida, K., Akamatsu, K., Tsuchiya, M., Nagasaka, A., and Yoshida, S. (1999) Isothiazolone deriv atives selectively inhibit telomerase from human and rat cancer cells in vitro. Biochemistry 38,11501 -11507.[CrossRef][Medline]
Heid, C.A., Stevens, J., Livak, K.J., and Williams, P.M.
(1996) Real time quan titative PCR. Genome
Res. 6,986
-994.
Henson, J.D., Neumann, A.A., Yeager, T.R., and Reddel, R.R. (2002) Alternative lengthening of telomeres in mammalian cells. Oncogene 21,598 -610.[CrossRef][Web of Science][Medline]
Hiraga, S., Ohnishi, T., Izumoto, S., Miyahara, E., Kanemura, Y.,
Matsumura, H., and Arita, N. (1998) Telomerase activity and
alterations in telomere length in human brain tumors. Cancer
Res. 58,2117
-2125.
Huber, H., Eggert, A., Janss, A.J., Wiewrodt, R., Zhao, H., Sutton, L.N., Rorke, L.B., Phillips, P.C., and Grotzer, M.A. (2001) Angiogenic profile of childhood primitive neuroectodermal brain tumours/medulloblastomas. Eur. J. Cancer 37,2064 -2072.
Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C.B., West, M.D.,
Ho, P.L., Coviello, G.M., Wright, W.E., Weinrich, S.L., and Shay, J.W.
(1994) Spe cific association of human telomerase activity with
immortal cells and cancer. Science
266,2011
-2015.
Kinjo, J., Nagao, T., Tanaka, T., Nonaka, G., Okawa, M., Nohara, T., and Okabe, H. (2002) Activity-guided fractionation of green tea extract with antiproliferative activity against human stomach cancer cells. Biol. Pharm. Bull. 25,1238 -1240.[CrossRef][Web of Science][Medline]
Langford, L.A., Piatyszek, M.A., Xu, R., Schold, S.C., Jr., and Shay, J.W. (1995) Telomerase activity in human brain tumours. Lancet 346,1267 -1268.[CrossRef][Web of Science][Medline]
Langford, L.A., Piatyszek, M.A., Xu, R., Schold, S.C., Jr., Wright, W.E., and Shay, J.W. (1997) Telomerase activity in ordinary meningiomas predicts poor outcome. Human Pathol. 28,416 -420.[CrossRef][Web of Science][Medline]
Lee, M.J., Wang, Z.Y., Li, H., Chen, L., Sun, Y., Gobbo, S., Balentine, D.A., and Yang, C.S. (1995) Analysis of plasma and urinary tea polyphenols in human subjects. Cancer Epidemiol. Biomarkers Prev. 4,393 -399.[Abstract]
Liu, J., Guo, L., Luo, Y., Li, J.W., and Li, H. (2000) All trans-retinoic acid sup presses in vitro growth and down-regulates LIF gene expression as well as telomerase activity of human medulloblastoma cells. Anticancer Res. 20,2659 -2664.[Web of Science][Medline]
Lyu, S.Y., Choi, S.H., and Park, W.B. (2002) Korean mistletoe lectin-induced apoptosis in hepatocarcinoma cells is associated with inhibition of telomerase via mitochondrial controlled pathway independent of p53. Arch. Pharm. Res. 25, 93-101.[Web of Science][Medline]
Mu, J., and Wei, L.X. (2002) Telomere and telomerase in oncology. Cell Res., 12, 1-7.[CrossRef][Web of Science][Medline]
Naasani, I., Seimiya, H., and Tsuruo, T. (1998) Telomerase inhibition, telom ere shortening, and senescence of cancer cells by tea catechins. Biochem. Biophys. Res. Commun. 249,391 -396.[CrossRef][Web of Science][Medline]
Naasani, I., Seimiya, H., Yamori, T., and Tsuruo, T.
(1999) FJ5002: A potent telomerase inhibitor identified by
exploiting the disease-oriented screen ing program with COMPARE analysis.
Cancer Res. 59,4004
-4011.
Naasani, I., Oh-Hashi, F., Oh-Hara, T., Feng, W.Y., Johnston, J.,
Chan, K., and Tsuruo, T. (2003) Blocking telomerase by dietary
polyphenols is a major mechanism for limiting the growth of human cancer cells
in vitro and in vivo. Cancer Res.
63,824
-830.
Nakagawa, K., and Miyazawa, T. (1997) Absorption and distribution of tea catechin, (-)-epigallocatechin-3-gallate, in the rat. J. Nutr. Sci. Vitaminol. (Tokyo) 43,679 -684.[Medline]
Neumann, A.A., and Reddel, R.R. (2002) Telomere maintenance and cancer— look, no telomerase. Nature Rev. Cancer 2,879 -884.[CrossRef][Web of Science][Medline]
Read, M.A., Wood, A.A., Harrison, J.R., Gowan, S.M., Kelland, L.R., Dosanjh, H.S., and Neidle, S. (1999) Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: Structure-activity relationships. J. Med. Chem. 42,4538 -4546.[CrossRef][Web of Science][Medline]
Sano, T., Asai, A., Mishima, K., Fujimaki, T., and Kirino, T. (1998) Telomerase activity in 144 brain tumours. Br. J. Cancer 77,1633 -1637.[Web of Science][Medline]
Shay, J.W., and Bacchetti, S. (1997) A survey of telomerase activity in human cancer. Eur. J. Cancer 33,787 -791.
Simon, M., Park, T.W., Leuenroth, S., Hans, V.H., Loning, T., and Schramm, J. (2000) Telomerase activity and expression of the telomerase catalytic subunit, hTERT, in meningioma progression. J. Neurosurg. 92,832 -840.[Web of Science][Medline]
Strahl, C., and Blackburn, E.H. (1996) Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortal ized human cell lines. Mol. Cell. Biol. 16, 53-65.[Abstract]
Suganuma, M., Okabe, S., Sueoka, N., Sueoka, E., Matsuyama, S., Imai, K., Nakachi, K., and Fujiki, H. (1999) Green tea and cancer chemoprevention. Mutat. Res. 428,339 -344.[Web of Science][Medline]
Wadhwa, R., Colgin, L., Yaguchi, T., Taira, K., Reddel, R.R., and
Kaul, S.C. (2002) Rhodacyanine dye MKT-077 inhibits in vitro
telomerase assay but has no detectable effects on telomerase activity in vivo.
Cancer Res. 62,4434
-4438.
White, L.K., Wright, W.E., and Shay, J.W. (2001) Telomerase inhibitors. Trends Biotechnol. 19,114 -120.[CrossRef][Web of Science][Medline]
Yang, C.S., Chen, L., Lee, M.J., and Landau, J.M. (1996) Effects of tea on carcinogenesis in animal models and humans. Adv. Exp. Med. Biol. 401, 51-61.[Medline]
Yang, C.S., and Wang, Z.Y. (1993) Tea and cancer.
J. Natl. Cancer Inst.
85,1038
-1049.
Yokoyama, Y., Takahashi, Y., Shinohara, A., Lian, Z., Wan, X.,
Niwa, K., and Tamaya, T. (1998) Attenuation of telomerase
activity by a hammerhead ribozyme targeting the template region of telomerase
RNA in endometrial carcinoma cells. Cancer Res.
58,5406
-5410.
Zuzak, T.J., Steinhoff, D.F., Sutton, L.N., Phillips, P.C., Eggert, A., and Grotzer, M.A. (2002) Loss of caspase-8 mRNA expression is common in childhood primitive neuroectodermal brain tumour/medulloblastoma. Eur. J. Cancer 38, 83-91.
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