Demonstration of Upregulated H2 Relaxin mRNA Expression during Neuroendocrine Differentiation of LNCaP Prostate Cancer Cells and Production of Biologically Active Mammalian Recombinant 6 Histidine‐Tagged H2 Relaxin

Figueiredo, Kevin A.; Palmer, Jodie; Mui, Alice; Nelson, Colleen C.; Cox, Michael

doi:10.1196/annals.1282.051

Cited by 14 publications

(18 citation statements)

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“…Similarly, relaxin is produced by the normal prostate (12)(13)(14)(15)(16), and expressed in prostate cancer cell lines LNCaP, DU145, and PC3 (17,18). Relaxin has been implicated in increased tumor growth and angiogenesis of PC3 prostate xenografts (19), whereas we have found that H2 relaxin expression is up-regulated in LNCaP cells undergoing neuroendocrine differentiation (20). Together, these studies strongly implicate relaxin in breast and prostate cancer progression.…”

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confidence: 52%

Relaxin Stimulates Leukocyte Adhesion and Migration through a Relaxin Receptor LGR7-dependent Mechanism

Figueiredo

Mui

Nelson

et al. 2006

Journal of Biological Chemistry

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Leukocytes are critical effectors of inflammation and tumor biology. Chemokine-like factors produced by such inflammatory sites are key mediators of tumor growth that activate leukocytic recruitment and tumor infiltration and suppress immune surveillance. Here we report that the endocrine peptide hormone, relaxin, is a regulator of leukocyte biology with properties important in recruitment to sites of inflammation. This study uses the human monocytic cell line THP-1 and normal human peripheral blood mononuclear cells to define a novel role for relaxin in regulation of leukocyte adhesion and migration. Our studies indicate that relaxin promotes adenylate cyclase activation, substrate adhesion, and migratory capacity of mononuclear leukocytes through a relaxin receptor LGR7-dependent mechanism. Relaxin-stimulated cAMP accumulation was observed to occur primarily in non-adherent cells. Relaxin stimulation results in increased substrate adhesion and increased migratory activity of leukocytes. In addition, relaxinstimulated substrate adhesion resulted in enhanced chemotaxis to monocyte chemoattractant protein-1. These responses in THP-1 and peripheral blood mononuclear cells are relaxin dose-dependent and proportional to cAMP accumulation. We further demonstrate that LGR7 is critical for mediating these biological responses by use of RNA interference lentiviral short hairpin constructs. In summary, we provide evidence that relaxin is a novel leukocyte stimulatory agent with properties affecting adhesion and chemomigration.Complex interactions between tumor cells and the immune system regulate disease progression by stimulating cell proliferation, neovascularization, tissue remodeling, and metastasis or by inhibiting the host anti-tumor immune response (1). However, the factors produced by tumor cells that affect their immune surveillance remain to be fully elucidated. The insulin-related peptide hormone, relaxin, possesses key features required of a tumor-derived factor capable of affecting malignant progression, and its emerging role as a putative mediator of tumor progression has been recently reviewed (2). In humans, relaxin is encoded by three genes designated H1, H2, and H3 (3). Functionally, relaxin is classically described to improve blood supply to multiple organs including the uterus, mammary gland, lung, and heart (4). Relaxin is also known to increase matrix metalloproteinase expression, resulting in collagen turnover of reproductive tissues and in models of fibrosis, and is responsible for lengthening of the interpubic ligament during delivery (3-5).A role for relaxin in cancer progression was first suggested 38 years ago by studies indicating that carcinogen-fed rats experienced substantially enhanced mammary tumor growth when co-treated with relaxin several weeks later (6). More recently, relaxin has been shown to support growth and invasiveness of breast cancer cells (7,8), and elevated relaxin serum levels are positively correlated with breast cancer metastases (9). Relaxin immunostaining has been dem...

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confidence: 52%

Relaxin Stimulates Leukocyte Adhesion and Migration through a Relaxin Receptor LGR7-dependent Mechanism

Figueiredo

Mui

Nelson

et al. 2006

Journal of Biological Chemistry

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“…These data show that relaxin plays a role in p53 R273H -facilitated AI CaP. Interestingly, H2 relaxin mRNA has been shown to be upregulated during neuroendocrine differentiation of LNCaP (Figueiredo et al, 2005). This group reported that induction of neuroendocrine differentiation using epinephrine and interleukin-6 resulted in a 1.5-fold increase in relaxin mRNA expression.…”

Section: Discussionmentioning

confidence: 76%

The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7

et al. 2006

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Mutations in p53 occur at a rate of approximately 70% in hormone-refractory prostate cancer (CaP), suggesting that p53 mutations facilitate the progression of CaP to androgen-independent (AI) growth. We have previously reported that transfection of p53 gain of function mutant alleles into LNCaP, an androgen-sensitive cell line, allows for AI growth of LNCaP in vitro. We herein confirm the in vivo relevance of those findings by demonstrating that the R273H p53 mutation (p53 R273H ) facilitates AI growth in castrated nude mice. In addition, we demonstrate that H2 relaxin is responsible for facilitating p53 R273H -mediated AI CaP. H2 relaxin is overexpressed in the LNCaP-R273H subline. Downregulation of H2 relaxin expression results in significant inhibition of AI growth, whereas addition of recombinant human H2 relaxin to parental LNCaP promotes AI growth. Inhibition of AI growth was also achieved by blocking expression of LGR7, the cognate receptor of H2 relaxin. Chromatin immunoprecipitation analysis was used to demonstrate that p53 R273H binds directly to the relaxin promoter, further confirming a role for H2 relaxin signaling in p53 R273H -mediated AI CaP. Lastly, we used a reporter gene assay to demonstrate that H2 relaxin can induce the expression of prostate-specific antigen via an androgen receptor-mediated pathway.

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“…We have studied the tumorigenic effect of RLN, a small peptide hormone produced both in the normal prostate and in prostate cancer (Figueiredo et al 2005, Silvertown et al 2006, Thompson et al 2006, Vinall et al 2006, Feng et al 2007, Liu et al 2008. Previously it has been shown that the RLN expression was increased in aggressive metastatic disease (Figueiredo et al 2005, Thompson et al 2006, Feng et al 2007, and that the stimulation of prostate cancer cells with RLN accelerated their invasiveness, adhesion, survival, and decreased cell apoptosis (Feng et al 2007). Moreover, in the TRAMP mouse model, transgenic overexpression of RLN decreased survival of the males with prostate cancer (Feng et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis

Feng

Agoulnik

Truong

et al. 2010

Endocrine-Related Cancer

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Relaxin (RLN) is a small peptide hormone expressed in several cancers of reproductive and endocrine organs. Increased expression of RLN in prostate cancer correlates with aggressive cancer. RLN G-protein-coupled receptor (RLN family peptide receptor 1, RXFP1) is expressed in both androgen receptor (AR)-positive and -negative prostate cancers as well as in prostate cancer cell lines. RLN behaves as a cell growth factor and increases invasiveness and proliferation of cancer cells in vitro and in vivo. The objective of this study is to determine whether downregulation of RXFP1 expression using small interfering RNA (siRNA) reduces cancer growth and metastasis in a xenograft model of prostate cancer. We used two well-characterized prostate adenocarcinoma cell lines, AR-positive LNCaP cells and AR-negative PC3 cells. The tumors were established in nude male mice by s.c. injections. Intratumoral injections of siRNAs loaded on biodegradable chitosan nanoparticles led to a downregulation of RXFP1 receptor expression and a dramatic reduction in tumor growth. In LNCaP tumors, the siRNA treatment led to an extensive necrosis. In PC3 xenografts treated with siRNA against RXFP1, the smaller tumor size was associated with the decreased cell proliferation and increased apoptosis. The downregulation of RXFP1 resulted in significant decrease in metastasis rate in PC3 tumors. Global transcriptional profiling of PC3 cells treated with RXFP1 siRNA revealed genes with significantly altered expression profiles previously shown to promote tumorigenesis, including the downregulation of MCAM, MUC1, ANGPTL4, GPI, and TSPAN8. Thus, the suppression of RLN/RXFP1 may have potential therapeutic benefits in prostate cancer.

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Demonstration of Upregulated H2 Relaxin mRNA Expression during Neuroendocrine Differentiation of LNCaP Prostate Cancer Cells and Production of Biologically Active Mammalian Recombinant 6 Histidine‐Tagged H2 Relaxin

Cited by 14 publications

References 18 publications

Relaxin Stimulates Leukocyte Adhesion and Migration through a Relaxin Receptor LGR7-dependent Mechanism

Relaxin Stimulates Leukocyte Adhesion and Migration through a Relaxin Receptor LGR7-dependent Mechanism

The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7

Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis

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