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

in Proceedings of the National Academy of Sciences of the United States of America by H Kiaris, A V Schally

TLDR

  • The study found that GH-RH antagonists can reduce the growth of tumors by decreasing the activity of a protein called telomerase. Telomerase is needed for tumors to grow, so when the activity of telomerase is reduced, the tumors grow slower. The study used mice and different types of cancer cells to test this idea. The study found that the GH-RH antagonist MZ-5-156 reduced the activity of telomerase in U-87MG glioblastomas and other types of cancer cells. The study also found that the GH-RH antagonist did not affect the levels of a protein called c-myc, which is also involved in tumor growth. The study suggests that the GH-RH antagonist works by reducing the activity of telomerase, which is needed for tumors to grow. Further studies are needed to see if this works in other types of tumors.

Abstract

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.

Overview

  • The study tests the hypothesis that the tumor inhibition induced by GH-RH antagonists is associated with a decrease in telomerase activity. The study uses nude mice bearing xenografts of U-87MG human glioblastomas and GH-RH antagonist MZ-5-156. Telomerase activity is assessed by the telomerase repeat amplification protocol. The study aims to establish whether GH-RH antagonists produce telomerase inhibition in other tumors.

Comparative Analysis & Findings

  • Treatment with MZ-5-156 reduced levels of telomerase activity as compared with controls in U-87MG glioblastomas. Addition of 3 microM MZ-5-156 also inhibited telomerase activity in H-69 small cell lung carcinomas, H-23 non-small cell lung carcinomas, and MDA-MB-468 breast carcinoma cells cultured in vitro. The repression of the telomerase activity was not accompanied by a significant decrease of mRNA level for the c-myc protooncogene that regulates telomerase.

Implications and Future Directions

  • The study suggests that tumor inhibition induced by 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.
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