Abstract
BackgroundAntagonists of growth hormone-releasing hormone (GHRH) are being developed for the treatment of various human cancers.MethodsMTT assay was used to test the proliferation of SKOV3 and CaOV3. The splice variant expression of GHRH receptors was examined by RT-PCR. The expression of protein in signal pathway was examined by Western blotting. siRNA was used to block the effect of EGFR.ResultsIn this study, we investigated the effects of a new GHRH antagonist JMR-132, in ovarian cancer cell lines SKOV3 and CaOV3 expressing splice variant (SV)1 of GHRH receptors. MTT assay showed that JMR-132 had strong antiproliferative effects on SKOV3 and CaOV3 cells in both a time-dependent and dose-dependent fashion. JMR-132 also induced the activation and increased cleaved caspase3 in a time- and dose-dependent manner in both cell lines. In addition, JMR-132 treatments decreased significantly the epidermal growth factor receptor (EGFR) level and the phosphorylation of Akt (p-Akt), suggesting that JMR-132 inhibits the EGFR-Akt pathway in ovarian cancer cells. More importantly, treatment of SKOV3 and CaOV3 cells with 100 nM JMR-132 attenuated proliferation and the antiapoptotic effect induced by EGF in both cell lines. After the knockdown of the expression of EGFR by siRNA, the antiproliferative effect of JMR-132 was abolished in SKOV3 and CaOV3 cells.ConclusionsThe present study demonstrates that the inhibitory effect of the GHRH antagonist JMR-132 on proliferation is due, in part, to an interference with the EGFR-Akt pathway in ovarian cancer cells.
Highlights
Antagonists of growth hormone-releasing hormone (GHRH) are being developed for the treatment of various human cancers
The expression of mRNA for GHRH receptors (GHRHR) SV1 in SKOV3 and CaOV3 cells Previous studies showed that GHRHR SV1 was expressed in different cancer cells
It has been reported that splice variants 1(SV1) of GHRH receptors was expressed in LNCaP cells [27,28,29]
Summary
Antagonists of growth hormone-releasing hormone (GHRH) are being developed for the treatment of various human cancers. Antagonists of growth hormone-releasing hormone (GHRH) are being developed for the treatment of various cancers [3,4]. GHRH antagonists were shown to inhibit the proliferation both in vivo and in vitro of various human cancers, including pancreatic [5], colorectal [6], prostatic [7,8,9,10], breast [11,12], renal [13], glioblastomas [14], osteosarcomas and Ewing sarcomas [15,16], lung carcinomas [17,18], lymphomas [19], as well as ovarian [20] and endometrial cancer [21]. The growth of various human cancers was suppressed without any involvement of the hypothalamic GHRH/pituitary GH/hepatic IGF-I axis [3]. The effect occurs through the disruption of the autocrine/paracrine production of IGF-I and/or IGF-II in tumors [3,24,25,26] by GHRH antagonists, or through the blockade of the stimulatory loop formed by tumoral GHRH and its receptors in tumors [3,27,28,29,30,31,32,33,34]
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