The expression of growth hormone-releasing hormone (GHRH) and splice variants of its receptor in human gastroenteropancreatic carcinomas

Abstract

Splice variants (SVs) of receptors for growth hormone-releasing hormone (GHRH) have been found in primary human prostate cancers and diverse human cancer cell lines. GHRH antagonists inhibit growth of various experimental human cancers, including pancreatic and colorectal, xenografted into nude mice or cultured in vitro, and their antiproliferative action could be mediated in part through SVs of GHRH receptors. In this study we examined the expression of mRNA for GHRH and for SVs of its receptors in tumors of human pancreatic, colorectal, and gastric cancer cell lines grown in nude mice. mRNA for both GHRH and SV1 isoform of GHRH receptors was expressed in tumors of pancreatic (SW1990, PANC-1, MIA PaCa-2, Capan-1, Capan-2, and CFPAC1), colonic (COLO 320DM and HT-29), and gastric (NCI-N87, HS746T, and AGS) cancer cell lines; mRNA for SV2 was also present in Capan-1, Capan-2, CFPAC1, HT-29, and NCI-N87 tumors. In proliferation studies in vitro, the growth of pancreatic, colonic, and gastric cancer cells was stimulated by GHRH(1-29)NH2 and inhibited by GHRH antagonist JV-1-38. The stimulation of some gastroenteropancreatic cancer cells by GHRH was followed by an increase in cAMP production, and GHRH antagonist JV-1-38 competitively inhibited this effect. Our study indicates the presence of an autocrine͞paracrine stimulatory loop based on GHRH and SV1 of GHRH receptors in human pancreatic, colorectal, and gastric cancers. The finding of SV1 receptor in human cancers provides an approach to an antitumor therapy based on the blockade of this receptor by specific GHRH antagonists.

Triple-negative breast cancers express receptors for growth hormone-releasing hormone (GHRH) and respond to GHRH antagonists with growth inhibition

“…The indirect, endocrine mechanism operates through the suppression of the GH release from the pituitary, and the resulting inhibition of the hepatic production of IGF-I [8,9]. In addition, it was observed that GHRH antagonists can inhibit the proliferation of diverse cancer lines by direct action in vitro, under conditions in which the contribution of the hypothalamic GHRH/pituitary GH/hepatic IGF-I axis is clearly excluded [8,[13][14][15][16][17][18][19][20][21][22][23][24][25]. These studies led to the conclusion that the main mechanism responsible for tumor inhibition could be a direct effect of the antagonists on the tumor tissue [8,11].…”

“…Accordingly, the expression of mRNA for GHRH or its peptide product were detected in surgical specimens of human endometrial, ovarian, breast and prostatic cancers [27,31,32]. mRNAs encoding four splice variants (SV) of GHRH receptors and specific high affinity binding sites for GHRH and its antagonistic analogs have been identified in diverse cell lines and specimens of human cancers [19,20,24,25,28,29,31,[33][34][35][36]. These findings suggest that the direct antiproliferative action of GHRH antagonists could be exerted through the disruption of an autocrine/paracrine stimulatory loop formed by tumoral GHRH and its receptors on tumors [14,19,20,28,29,35,37,38].…”

Knocking down gene expression for growth hormone-releasing hormone inhibits proliferation of human cancer cell lines

“…Growth hormone-releasing hormone antagonists suppress the in vivo growth of various experimental cancers such as prostatic (Zarandi et al, 2006;Stangelberger et al, 2007), mammary (Buchholz et al, 2007), ovarian (Chatzistamou et al, 2001), renal cell carcinomas , small cell lung carcinomas (Hohla et al, 2006), pancreatic and colorectal carcinomas (Szepeshazi et al, 2000;Busto et al, 2002), endometrial (Engel et al, 2005), osteogenic sarcomas (Braczkowski et al, 2002) as well as malignant glioblastomas (Jaeger et al, 2005).…”

The expression of the pituitary growth hormone-releasing hormone receptor and its splice variants in normal and neoplastic human tissues

“…Our group demonstrated that GHRH antagonists can inhibit tumor growth through indirect and direct pathways (2)(3)(4)(5)(6)(7). The indirect mechanism is based on the suppression of the pituitary GH-hepatic insulin-like growth factor (IGF)-I axis.…”