Decrease in telomerase activity in U-87MG human glioblastomas after treatment with an antagonist of growth hormone-releasing hormone

被引:70
作者
Kiaris, H
Schally, AV
机构
[1] Vet Affairs Med Ctr, Inst Endocrine Polypeptide & Canc, New Orleans, LA 70112 USA
[2] Tulane Univ, Sch Med, Sect Expt Med, New Orleans, LA 70112 USA
关键词
telomerase repeat amplification assay; telomerase catalytic subunit regulation; tumor regression; down-regulation of telomerase gene;
D O I
10.1073/pnas.96.1.226
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Antagonists of growth hormone-releasing hormone (GH-RH) inhibit the growth of various turners 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 mu M MZ-5-156 also inhibited telomerase activity. Reverse transcription-PCR analysis revealed that in U-87MG glioblrastomas, 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.
引用
收藏
页码:226 / 231
页数:6
相关论文
共 47 条
[1]   INSULIN, INSULIN-LIKE GROWTH FACTOR-I AND PLATELET-DERIVED GROWTH-FACTOR INTERACT ADDITIVELY IN THE INDUCTION OF THE PROTOONCOGENE C-MYC AND CELLULAR PROLIFERATION IN CULTURED BOVINE AORTIC SMOOTH-MUSCLE CELLS [J].
BANSKOTA, NK ;
TAUB, R ;
ZELLNER, K ;
KING, GL .
MOLECULAR ENDOCRINOLOGY, 1989, 3 (08) :1183-1190
[2]   Somatostatin and growth hormone-releasing hormone in normal and tumoral human breast tissue: Endogenous content, in vitro pulsatile release, and regulation [J].
Benlot, C ;
Levy, L ;
Fontanaud, P ;
Roche, A ;
Rouannet, P ;
Joubert, D .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 1997, 82 (02) :690-696
[3]   SEQUENCE OF THE MURINE AND HUMAN CELLULAR MYC ONCOGENES AND 2 MODES OF MYC TRANSCRIPTION RESULTING FROM CHROMOSOME-TRANSLOCATION IN B-LYMPHOID TUMORS [J].
BERNARD, O ;
CORY, S ;
GERONDAKIS, S ;
WEBB, E ;
ADAMS, JM .
EMBO JOURNAL, 1983, 2 (12) :2375-2383
[4]   STRUCTURE AND FUNCTION OF TELOMERES [J].
BLACKBURN, EH .
NATURE, 1991, 350 (6319) :569-573
[5]   Extension of life-span by introduction of telomerase into normal human cells [J].
Bodnar, AG ;
Ouellette, M ;
Frolkis, M ;
Holt, SE ;
Chiu, CP ;
Morin, GB ;
Harley, CB ;
Shay, JW ;
Lichtsteiner, S ;
Wright, WE .
SCIENCE, 1998, 279 (5349) :349-352
[6]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[7]   Telomere dynamics and telomerase activity in in vitro immortalised human cells [J].
Bryan, TM ;
Reddel, RR .
EUROPEAN JOURNAL OF CANCER, 1997, 33 (05) :767-773
[8]   TELOMERE ELONGATION IN IMMORTAL HUMAN-CELLS WITHOUT DETECTABLE TELOMERASE ACTIVITY [J].
BRYAN, TM ;
ENGLEZOU, A ;
GUPTA, J ;
BACCHETTI, S ;
REDDEL, RR .
EMBO JOURNAL, 1995, 14 (17) :4240-4248
[9]   Insulin-like growth factor I induction of c-myc expression in bovine fibroblasts can be blocked by antecedent insulin receptor activation [J].
Conover, CA ;
Bale, LK .
EXPERIMENTAL CELL RESEARCH, 1998, 238 (01) :122-127
[10]  
DAUGHADAY WH, 1990, ENDOCRINOLOGY, V127, P1