Decrease in telomerase activity in U-87MG human glioblastomas after treatment with an antagonist of growth hormone-releasing hormone.
Antagonists of growth hormone-releasing hormone (GH-RH) inhibit the growth of various tumors through mechanisms that involve the suppression of the insulin-like growth factor I and/or insulin-like growth factor II levels or secretion. In the present study, we tested the hypothesis that the tumor inhibition is associated with a decrease in telomerase activity because telomerase is considered obligatory for continued tumor growth. Nude mice bearing xenografts of U-87MG human glioblastomas were treated with GH-RH antagonist MZ-5-156. Telomerase activity was assessed by the telomerase repeat amplification protocol. Treatment with MZ-5-156 reduced levels of telomerase activity as compared with controls. When U-87 glioblastomas, H-69 small cell lung carcinomas, H-23 non-small cell lung carcinomas, and MDA-MB-468 breast carcinoma cells were cultured in vitro, addition of 3 microM MZ-5-156 also inhibited telomerase activity. Reverse transcription-PCR analysis revealed that in U-87MG glioblastomas, the expression of the hTRT gene encoding for the telomerase catalytic subunit was significantly decreased by MZ-5-156, whereas the levels of mRNA for hTR and TP1, which encode for the telomerase RNA and telomerase-associated protein, respectively, were unaffected. The repression of the telomerase activity was not accompanied by a significant decrease of mRNA level for the c-myc protooncogene that regulates telomerase. Our findings suggest that tumor inhibition induced by the GH-RH antagonists in U-87MG glioblastomas is associated with the down-regulation of the hTRT gene, resulting in a decrease in telomerase activity. Further studies are needed to establish whether GH-RH antagonists produce telomerase inhibition in other tumors.
Kiaris
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Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70112-1262, USA.
Schally
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D000818:Animals; D005909:Glioblastoma / Q000201:enzymology*; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000201:enzymology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019098:Telomerase / Q000032:analysis* / Q000235:genetics; D014407:Tumor Cells, Cultured
C106656:MZ 5-156; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; D019098:Telomerase