Growth hormone receptor modulators

Birzniece, Vita; Sata, Akira; Ho, Ken K. Y.

doi:10.1007/s11154-008-9089-x

Cited by 54 publications

(36 citation statements)

References 136 publications

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“…On the other hand, estrogens were shown to inhibit signaling of GH-receptors by suppressing GH-dependent JAK phosphorylation. This effect is exerted by induction of SOCS expression by estradiol, a known negative regulator of signaling of several cytokine receptors (23). But vice versa GH also influences effects of estrogens via GPER expression as shown in the present report.…”

Section: Discussionsupporting

confidence: 69%

Inhibition of growth hormone receptor by Somavert reduces expression of GPER and prevents growth stimulation of triple‑negative breast cancer by 17β‑estradiol

Girgert¹,

Emons²,

Gründker³

2018

Oncol Lett

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Abstract. Currently, conventional chemotherapy is the only treatment option for triple-negative breast cancers (TNBC) due to a lack of a unique target. In TNBC, a high expression of the membrane bound G protein-coupled estrogen receptor (GPER), correlates with a worse outcome. There is a potential for an association between growth hormone receptor (GHR) and GPER expression. To confirm this hypothesis, GHR was inhibited in TNBC cells with Somavert, and GPER expression levels, and the effect on signal transduction and proliferation induction in TNBC cells were analyzed. Proliferation of TNBC cells was measured using an Alamar-blue assay. Expression of GPER and activation of c-src and epidermal growth factor receptor (EGFR) by 17β-estradiol was analyzed by western blotting. Induction of c-fos, cyclin D1 and aromatase expression was determined by reverse transcription-semi-quantitative polymerase chain reaction. The expression of GPER was concentration-and time-dependently reduced by Somavert down to 46±7% (P<0.01) of the control. Furthermore, 17β-estradiol significantly increased the cell number of HCC1806 cells to 128±14% (P<0.05), and that of MDA-MB-453 cells to 115±3%. This increase in cell number was reduced to 103±11% in HCC1806 cells in which GPER expression was downregulated by Somavert, and to 102±3% in MDA-MB-453 cells. In addition, 17β-estradiol increased the activation of c-src in HCC1806 cells by 1.8-fold, and Somavert reduced p-src to 63% of control. In MDA-MB-453 cells src phosphorylation increased by 7-fold upon stimulation with estradiol, but after treatment with Somavert only a 4-fold increase was observed. Phosphorylation of EGFR was increased by 2.2-fold of control in HCC1806 cells by 17β-estradiol, and by 1.4-fold in MDA-MD-453 cells. Somavert completely prevented this activation. Induction of cyclin D1 and aromatase expression by 17β-estradiol was also prevented by Somavert. Somavert reduces GPER expression in triple negative breast cancer cells. Treatment with Somavert prevents induction of genes regulating proliferation by 17β-estradiol. Inhibition of GPER expression is a promising therapeutic intervention for TNBC.

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Section: Discussionsupporting

confidence: 69%

Inhibition of growth hormone receptor by Somavert reduces expression of GPER and prevents growth stimulation of triple‑negative breast cancer by 17β‑estradiol

Girgert¹,

Emons²,

Gründker³

2018

Oncol Lett

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“…Activated JAKs are capable of initiating a multitude of signaling cascades, including major signaling pathways such as JAK/STAT, PI3K/Akt, and p38 MAPK pathways (32,33). Like activation of other MAPKs, p38 MAPK activation is regulated posttranslationally by phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Janus Kinase 3 Activity Is Necessary for Phosphorylation of Cytosolic Phospholipase A2 and Prostaglandin E2 Synthesis by Macrophages Infected with Francisella tularensis Live Vaccine Strain

et al. 2014

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Francisella tularensis, the causative agent of tularemia, modulates the host immune response to gain a survival advantage within the host. One mechanism of immune evasion is the ability of F. tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 (PGE 2 ), which alters the host T cell response making the host more susceptible to Francisella growth. PGE 2 is synthesized by a tightly regulated biosynthetic pathway following stimulation. The synthesis of PGE 2 begins with the liberation of arachidonic acid (AA) from membrane phospholipids by cytosolic phospholipase A2 (cPLA 2 ). AA is subsequently converted to the unstable intermediate PGH 2 by cyclooxygenase-2 (COX-2), and PGH 2 undergoes an isomerization reaction to generate PGE 2 . Our objective was to identify F. tularensis-activated host signaling pathways that regulate the activity of the enzymes in the PGE 2 -biosynthetic pathway. In this study, we show that cPLA 2 , p38 mitogen-activated protein kinase (MAPK), and Janus kinase 3 (JAK3) signaling are necessary for F. tularensis-induced PGE 2 production. Inhibition of JAK3 activity reduced the phosphorylation of cPLA 2 and COX-2 protein levels. In addition, JAK3 regulates cPLA 2 phosphorylation independent of transcription. Moreover, p38 MAPK activity is required for F. tularensis-induced COX-2 protein synthesis, but not for the phosphorylation of cPLA 2 . This research highlights a unique signaling axis in which JAK3 and p38 MAPK regulate the activity of multiple enzymes of the PGE 2 -biosynthetic pathway in macrophages infected with F. tularensis.

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“…At cellular level, SOCS expression is well documented to serve as the feedback repressor for cytokine signaling via inhibition of JAK/ STAT pathway (Croker et al 2008) and plays a protective role in preventing hyperactivation of immune system, which can lead to autoimmune/inflammatory disorders (Liang et al 2014). In mammals, SOCS proteins can also act as negative modulators for growth hormone (GH) actions (Birzniece et al 2009) and contribute to the cross talk between immune system and somatotropic axis (Ahmed & Farquharson 2010). In rodents, GH treatment is known to induce Socs2, Socs3, and Cish expression in the liver, both in vivo and in vitro (Adams et al 1998, TolletEgnell et al 1999.…”

Section: Introductionmentioning

confidence: 99%

Type II SOCS as a feedback repressor for GH-induced Igf1 expression in carp hepatocytes

Jiang

Jia

et al. 2016

Journal of Endocrinology

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Type II suppressor of cytokine signaling (SOCS) serve as feedback repressors for cytokines and are known to inhibit growth hormone (GH) actions. However, direct evidence for SOCS modulation of GH-induced insulin-like growth factor 1 (Igf1) expression is lacking, and the post-receptor signaling for SOCS expression at the hepatic level is still unclear. To shed light on the comparative aspects of SOCS in GH functions, grass carp was used as a model to study the role of type II SOCS in GH-induced Igf1 expression. Structural identity of type II SOCS, Socs1-3 and cytokine-inducible SH2-containing protein (Cish), was established in grass carp by 5'/3'-RACE, and their expression at both transcript and protein levels were confirmed in the liver by RT-PCR and LC/MS/MS respectively. In carp hepatocytes, GH treatment induced rapid phosphorylation of JAK 2 , STATs, MAPK, PI3K, and protein kinase B (Akt) with parallel rises in socs1-3 and cish mRNA levels, and these stimulatory effects on type II SOCS were shown to occur before the gradual loss of igf1 gene expression caused by prolonged exposure of GH. Furthermore, GH-induced type II SOCS gene expression could be negated by inhibiting JAK 2 , STATs, MEK 1/2 , P 38 MAPK , PI3K, and/or Akt respectively. In CHO cells transfected with carp GH receptor, over-expression of these newly cloned type II SOCS not only suppressed JAK 2 /STAT 5 signaling with GH treatment but also inhibited GH-induced grass carp Igf1 promoter activity. These results, taken together, suggest that type II SOCS could be induced by GH in the carp liver via JAK 2 /STATs, MAPK, and PI3K/Akt cascades and serve as feedback repressors for GH signaling and induction of igf1 gene expression.

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Growth hormone receptor modulators

Cited by 54 publications

References 136 publications

Inhibition of growth hormone receptor by Somavert reduces expression of GPER and prevents growth stimulation of triple‑negative breast cancer by 17β‑estradiol

Inhibition of growth hormone receptor by Somavert reduces expression of GPER and prevents growth stimulation of triple‑negative breast cancer by 17β‑estradiol

Janus Kinase 3 Activity Is Necessary for Phosphorylation of Cytosolic Phospholipase A2 and Prostaglandin E2 Synthesis by Macrophages Infected with Francisella tularensis Live Vaccine Strain

Type II SOCS as a feedback repressor for GH-induced Igf1 expression in carp hepatocytes

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