The effect of a novel antagonist of growth hormone releasing hormone on cell proliferation and on the key cell signaling pathways in nine different breast cancer cell lines

Abstract

Abstract. Growth hormone releasing hormone (GHRH) antagonists have been developed for the treatment of various cancers. We investigated the effects of a novel GHRH antagonist, MIA-602, on nine breast cancer cell lines, differing in their expression for estrogen-, progesterone-and HER-2 receptors. We detected the presence of pituitary-type GHRH receptors (pGHRH-R) on 6 of the 9 breast cancer cell lines. The main splice variant of pGHRH-R, SV1, was found on all 9 cell lines. MTT assay showed that following treatment with MIA-602, cell viability decreased significantly in all 9 cell lines. The reduction in cell viability was greater in cells positive for both pGHRH-R and SV1, than in cells positive for only SV1, but the difference was not significant. Using Western blotting, we demonstrated that the levels of phosphoAkt, -GSK3β and -ERK1/2 decreased significantly following exposure to MIA-602 and the level of phospho-p38 increased after treatment. The reduction of the phosphorylated antiapoptotic proteins was significantly greater in cells where both pGHRH-R and SV1 were present, than where only SV1 was expressed. In conclusion, our study shows that MIA-602 is effective against a wide range of breast cancer cells in vitro, independently of their receptor positivity, suggesting the potential use of GHRH antagonists also in the treatment of triple-negative breast cancer. The effect of MIA-602 was mediated nearly as well in tumors that expressed only the SV1 receptor compared to those in which both SV1 and pGHRH-R were present, although a difference could be detected at the level of cell signaling.

Anti-proliferative and pro-apoptotic effects of GHRH antagonists in prostate cancer

“…The results confirmed that GHRH antagonists significantly decreased viability in the three cell lines studied. A reduction of viability has been described in breast and prostate tumor cells with the antagonist JMR-132 [22, 23] as well as in other cell types with other GHRH antagonists [10, 24–27]. Since the variations in metabolic activity provoked by GHRH antagonists may be due to mitogenic changes, we performed proliferation assays on the three cell lines.…”

Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers

“…Several reports have detailed the effects of treatment with GHRH antagonists on the growth of breast cancers. [ 16 , 28 , 46 , 47 ] However, the role of GHRH in the regulation of inflammatory cytokine expression in triple negative breast cancer has not been fully investigated. This study illustrates the benefits of using GHRH antagonists for the treatment of cancers which are highly treatment-resistant.…”

“…[ 16 , 17 ] Growth hormone subsequently stimulates the release of hepatic insulin-like growth factor, which is a major anabolic growth factor and a potent mitogen for many neoplasms. [ 17 - 20 ] Biologically active GHRH, mRNA for GHRH, GHRH receptors (GHRH-R), and GHRH-R splice variants have been identified in surgical specimens and tumor cell lines of a multitude of human cancers, including various types of breast cancer [ 21 - 28 ]. GHRH acts as an autocrine/paracrine growth factor in human cancers [ 16 , 29 - 31 ] including breast [ 32 ].…”

Antagonistic analogs of growth hormone-releasing hormone increase the efficacy of treatment of triple negative breast cancer in nude mice with doxorubicin; A preclinical study

“…Several reports have detailed the effects of treatment with GHRH antagonists on the growth of breast cancers. [ 6 , 20 , 57 , 58 ] The study presented herein illustrates the role of GHRH signaling in the regulation of drug resistance in TNBC. Our results also demonstrate the ability of a GHRH antagonist, MIA-602, to be a potential new treatment for drug resistant cancers.…”