Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation

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Retinoblastoma (RB) is the most common intraocular cancer in children worldwide. Current treatments mainly involve combinations of chemotherapies, cryotherapies, and laser-based therapies. Severe or late-stage disease may require enucleation or lead to fatality. Recently, RB has been shown to arise from cone precursor cells, which have high MDM2 levels to suppress p53-mediated apoptosis. This finding leads to the hypothesis that restoring apoptosis mechanisms in RBs could specifically kill the cancer cells without affecting other retinal cells. We have previously reported involvement of an extrapituitary signaling pathway of the growth hormone-releasing hormone (GHRH) in the retina. Here we show that the GHRH receptor (GHRH-R) is highly expressed in RB cells but not in other retinal cells. We induced specific apoptosis with two different GHRH-R antagonists, MIA-602 and MIA-690. Importantly, these GHRH-R antagonists do not trigger apoptosis in other retinal cells such as retinal pigmented epithelial cells. We delineated the gene expression profiles regulated by GHRH-R antagonists and found that cell proliferation genes and apoptotic genes are down-and up-regulated, respectively. Our results reveal the involvement of GHRH-R in survival and proliferation of RB and demonstrate that GHRH-R antagonists can specifically kill the RB cells.GHRH pathway | GHRH-R antagonist | retinoblastoma | growth hormonereleasing hormone | apoptosis R etinoblastoma (RB) is the most common childhood intraocular malignancy and accounts for approximately 3% of all childhood cancers (1). It has been reported to arise from the cone precursor cells of the retina that transduce light into electrical signals (2). RB is thought to result largely from the loss of function of both copies of RB1 gene located on human chromosome 13q14 (3, 4). Functional disruption of RB1 can be generated by the somatic inactivation of both RB1 alleles, or with a germline RB1 mutation in one allele and a somatic inactivation of the second RB1 allele (5). The RB1 protein acts as a signal transducer connecting cell cycle progression with the transcription machinery (6). There are four steps in the mitotic cycle of a cell: G1, S, G2, and cell division. In the G1 phase, cyclin D is highly expressed, which leads to activation of cyclin-dependent kinases (CDKs) 4 and 6. CDK4 and CDK6 then phosphorylate RB1, inhibiting RB1 binding to the transcription factor E2F (7, 8). As a result, the RB1-free E2F binds to promotors of several genes and turns on their expressions to induce cell cycle progression into S phase, the DNA synthesis phase. Similarly, cells carrying RB1 mutations would also progress into S phase. Normally, this premature progression into S phase would trigger apoptosis to prevent uncontrolled cell proliferation (9). However, it has been reported that the cone precursor cells express high levels of MDM2, a protein that suppresses apoptosis mediated by p53 (2). Therefore, cone precursor cells in patients carrying RB1 mutations pass through the cell cycle faster an...

supporting

confidence: 56%

Section: Discussionmentioning

confidence: 96%

Section: Significancementioning

confidence: 99%

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Antagonists of growth hormone-releasing hormone receptor induce apoptosis specifically in retinoblastoma cells

Chu

Law

Chan

et al. 2016

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“…MIA-602 inhibited NF-κB in glioblastoma, breast cancer, and ovarian cancer (37). Most recently, MIA-602 was shown to inactivate STAT3 in mouse bone marrow-derived mesenchymal stem cells (50) and to down-regulate the expression of inflammatory cytokines in experimental ocular inflammation (38) and triplenegative breast cancer (14).…”

Section: Discussionmentioning

confidence: 99%

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

Gan

Jiang

et al. 2016

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Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.GHRH receptor | GHRH-R antagonist | PAK1 | stomach cancer | prognostic predictor

“…Anti-inflammatory effects for GHRH antagonists were also demonstrated in experimental models of cancer and ocular inflammation (39,40).…”

Section: Significancementioning

confidence: 93%

Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells

Popovics

Salgueiro

Kovacs

et al. 2017

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The etiology of benign prostatic hyperplasia (BPH) is multifactorial, and chronic inflammation plays a pivotal role in its pathogenesis. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that has been shown to act as paracrine/autocrine factor in various malignancies including prostate cancer. GHRH and its receptors are expressed in experimental models of BPH, in which antagonists of GHRH suppressed the levels of proinflammatory cytokines and altered the expression of genes related to epithelial-to-mesenchymal transition (EMT). We investigated the effects of GHRH antagonist on prostatic enlargement induced by inflammation. Autoimmune prostatitis in Balb/C mice was induced by a homogenate of reproductive tissues of male rats. During the 8-wk induction of chronic prostatitis, we detected a progressive increase in prostatic volume reaching 92% at week 8 compared with control (P < 0.001). Daily treatment for 1 mo with GHRH antagonist MIA-690 caused a 30% reduction in prostate volume (P < 0.05). Conditioned medium derived from macrophages increased the average volume of spheres by 82.7% (P < 0.001) and elevated the expression of mRNA for N-cadherin, Snail, and GHRH. GHRH antagonist reduced the average volume of spheres stimulated by inflammation by 75.5% (P < 0.05), and TGF-β2 by 91.8% (P < 0.01). The proliferation of primary epithelial cells stimulated by IL-17A or TGF-β2 was also inhibited by 124.1% and 69.9%, respectively. GHRH stimulated the growth of BPH-1 and primary prostate spheres. This study provides evidence that GHRH plays important roles in prostatic inflammation and EMT and suggests the merit of further investigation to elucidate the effects of GHRH antagonists in prostatitis and BPH. chronic prostatic inflammation | neuropeptide | prostatic hyperplasia | targeted therapy | experimental autoimmune prostatitis