Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone

Lin Zhao, Tetsu Yano, Yutaka Osuga, Shunsuke Nakagawa, Hajime Oishi, Osamu Wada-Hiraike, Xiaohui Tang, Naomi Yano, Koji Kugu, Andrew V Schally, Yuji Taketani

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The expression of growth hormone-releasing hormone (GHRH) and its receptors has been demonstrated in peripheral tissues as well as CNS. Recently, the functional splice variant SV1 of GHRH receptor was identified in various human cancers and cancer cell lines. Although antineoplastic activity of GHRH antagonists has been clearly demonstrated, the mechanism of action is incompletely understood. The objective of this study was the investigation of direct anti-proliferative effect of GHRH antagonist MZ-5-156 on HEC-1A human endometrial cancer cell line and the elucidation of underlying mechanisms. RT-PCR revealed the expression of mRNA for GHRH and SV1 of GHRH receptor in HEC-1A cells. MZ-5-156, at concentrations between 10-7 and 10-5 M, had a dose-dependent antiproliferative effect on HEC-1A cells, as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium, (MTS) assay. Hoechst 33342 staining and flow cytometric analysis indicated that MZ-5-156, at 10-6 M, induced apoptosis in HEC-1A cells after 48 h of treatment. Western blot analysis of apoptosis-related proteins demonstrated that treatment with MZ-5-156 (10-6 M) for 48 h significantly increased the protein levels of Fas, phospho-p53 (Ser46), p53AIP1 (p53-regulated Apoptosis-Inducing Protein 1), and caspase-8, -9, and -3, and decreased the protein level of Bcl-2. These results demonstrate that MZ-5-156 can directly inhibit the proliferation of human endometrial cancer cells, which express mRNA for GHRH and SV1 of GHRH receptor, presumably through the induction of p53-dependent apoptosis coupled with the up-regulation of Fas, phospho-p53 (Ser46), p53AIP1, and caspase-8, -9, and -3, and the down-regulation of Bcl-2.

Original languageEnglish
Pages (from-to)593-601
Number of pages9
JournalInternational Journal of Oncology
Volume32
Issue number3
StatePublished - Mar 1 2008

Fingerprint

Growth Hormone-Releasing Hormone
Endometrial Neoplasms
Cell Line
Hormone Antagonists
Growth
Apoptosis Regulatory Proteins
Caspase 9
Caspase 8
Apoptosis
Messenger RNA
Proteins
Antineoplastic Agents
Neoplasms
Up-Regulation
Down-Regulation
Western Blotting
MZ 5-156
Staining and Labeling
Polymerase Chain Reaction
somatotropin releasing hormone receptor

Keywords

  • Apoptosis
  • Endometrial cancer
  • Growth hormone-releasing hormone antagonist
  • p53

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Zhao, L., Yano, T., Osuga, Y., Nakagawa, S., Oishi, H., Wada-Hiraike, O., ... Taketani, Y. (2008). Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone. International Journal of Oncology, 32(3), 593-601.

Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone. / Zhao, Lin; Yano, Tetsu; Osuga, Yutaka; Nakagawa, Shunsuke; Oishi, Hajime; Wada-Hiraike, Osamu; Tang, Xiaohui; Yano, Naomi; Kugu, Koji; Schally, Andrew V; Taketani, Yuji.

In: International Journal of Oncology, Vol. 32, No. 3, 01.03.2008, p. 593-601.

Research output: Contribution to journalArticle

Zhao, L, Yano, T, Osuga, Y, Nakagawa, S, Oishi, H, Wada-Hiraike, O, Tang, X, Yano, N, Kugu, K, Schally, AV & Taketani, Y 2008, 'Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone', International Journal of Oncology, vol. 32, no. 3, pp. 593-601.
Zhao, Lin ; Yano, Tetsu ; Osuga, Yutaka ; Nakagawa, Shunsuke ; Oishi, Hajime ; Wada-Hiraike, Osamu ; Tang, Xiaohui ; Yano, Naomi ; Kugu, Koji ; Schally, Andrew V ; Taketani, Yuji. / Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone. In: International Journal of Oncology. 2008 ; Vol. 32, No. 3. pp. 593-601.
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