Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis

Feng, Shi Ting; Agoulnik, Irina U.; Truong, Anne; Li, Zhen; Creighton, Chad J.; Kaftanovskaya, Elena M.; Pereira, R.M.; Han, Hee Dong; López-Berestein, Gabriel; Klonisch, Thomas; Ittmann, Michael; Sood, Anil K.; Agoulnik, Alexander I.

doi:10.1677/erc-10-0073

Cited by 74 publications

(77 citation statements)

References 45 publications

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“…An elevated ANGPTL4 in CRCs is also correlated with shorter disease-free survival rates (25). Furthermore, the (11,35,36). In contrast, studies have also shown that increased ANGPTL4 expression inhibits melanoma, lung, and colorectal tumor growth, metastasis, and angiogenesis (10,37).…”

Section: Angptl4 Expression and Its Transcriptional Regulation In Hummentioning

confidence: 97%

Emerging Roles of Angiopoietin-like 4 in Human Cancer

Tan

Teo

Sng

et al. 2012

Molecular Cancer Research

155

166

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Angiopoietin-like 4 (ANGPTL4) is best known for its role as an adipokine involved in the regulation of lipid and glucose metabolism. The characterization of ANGPTL4 as an adipokine is largely due to our limited understanding of the interaction partners of ANGPTL4 and how ANGPTL4 initiates intracellular signaling. Recent findings have revealed a critical role for ANGPTL4 in cancer growth and progression, anoikis resistance, altered redox regulation, angiogenesis, and metastasis. Emerging evidence suggests that ANGPTL4 function may be drastically altered depending on the proteolytic processing and posttranslational modifications of ANGPTL4, which may clarify several conflicting roles of ANGPTL4 in different cancers. Although the N-terminal coiled-coil region of ANGPTL4 has been largely responsible for the endocrine regulatory role in lipid metabolism, insulin sensitivity, and glucose homeostasis, it has now emerged that the COOH-terminal fibrinogen-like domain of ANGPTL4 may be a key regulator in the multifaceted signaling during cancer development. New insights into the mechanistic action of this functional domain have opened a new chapter into the possible clinical application of ANGPTL4 as a promising candidate for clinical intervention in the fight against cancer. This review summarizes our current understanding of ANGPTL4 in cancer and highlights areas that warrant further investigation. A better understanding of the underlying cellular and molecular mechanisms of ANGPTL4 will reveal novel insights into other aspects of tumorigenesis and the potential therapeutic value of ANGPTL4. Mol Cancer Res; 10(6); 677-88. Ó2012 AACR.

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Section: Angptl4 Expression and Its Transcriptional Regulation In Hummentioning

confidence: 97%

Emerging Roles of Angiopoietin-like 4 in Human Cancer

Tan

Teo

Sng

et al. 2012

Molecular Cancer Research

155

166

View full text Add to dashboard Cite

show abstract

“…Specific RXFP1 and negative control siRNA were supplied by Qiagen (Valencia, CA). The siRNA sequence used for RXFP1 gene silencing (siRXFP1) was GGAUGUCAAGUGCUCCCUUtt (sense strand) (13,17). Negative control siRNA (siNC) with no significant sequence similarity to human gene sequences was used as control.…”

Section: Matrigel Invasion Assay Bd Biocoat Matrigel Invasionmentioning

confidence: 99%

“…Negative control siRNA (siNC) with no significant sequence similarity to human gene sequences was used as control. The PC3 cells were transfected with siRXFP1 and siNC (5 µg each) using Nucleofector device as previously described (17). Transfected cells were harvested after 72 h, the protein was extracted from the total cell lysate for Western blot experiments.…”

Section: Matrigel Invasion Assay Bd Biocoat Matrigel Invasionmentioning

confidence: 99%

“…We have shown that systemic transgenic overexpression of relaxin in mice decreased survival of TRAMP (transgenic adenocarcinoma of mouse prostate) mutant males (13). Treatment of prostate cancer xenografts with chitosan nanoparticles containing siRNA targeting RXFP1 decreased tumor growth and number of metastases (17).…”

Section: Introductionmentioning

confidence: 99%

“…Modulations of relaxin signaling affect cell proliferation, apoptosis, cell migration, invasiveness, adhesion and other cell characteristics important in the context of normal development as well as in oncogenic transformation. In the last several years the potential role of relaxin in prostate cancer tumorigenesis was under investigation (10)(11)(12)(13)(14)(15)(16)(17). Relaxin and RXFP1 are well-expressed in normal epithelial prostate cells as well as in prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Expression of LDL-A module of relaxin receptor in prostate cancer cells inhibits tumorigenesis

Feng

Agoulnik

2011

Int J Oncol

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Abstract. Peptide hormone relaxin produced in normal and cancer prostate cells can stimulate prostate cancer progression. Suppression of relaxin or relaxin receptor RXFP1 expression inhibited prostate cancer both in vitro and in vivo. RXFP1 is a G protein-coupled receptor with the extracellular low density lipoprotein A (LDL-A) module located at the N-terminus. The LDL-A module exhibits a competitive inhibition effect on the RXFP1 function and might be used to suppress relaxin signaling. In this study, we investigated the effect of LDL-A overexpression on prostate cancer cells. PC3 cells expressing the RXFP1-LDL-A module had a decreased proliferation, soft agar colony formation, adhesion, invasion in vitro, and grew at a slower rate than control cells as tumors in xenograft models in mice. Expression analysis revealed that the RXFP1-LDL-A expression in PC3 cells inhibited Akt phosphorylation and MMP2 activation, and led to the down-regulation of several genes previously implicated in tumorigenesis, such as MMP28, S100P, IGFBP2, MUC1 and S100A4. These results indicate that the inhibition of RXFP1 by peptide based on the LDL-A module of this receptor may be a potential approach for prostate cancer suppression.

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Novel CTRP8‐RXFP1‐JAK3‐STAT3 axis promotes Cdc42‐dependent actin remodeling for enhanced filopodia formation and motility in human glioblastoma cells

et al. 2021

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C1q tumor necrosis factor-related peptide 8 (CTRP8) is the least studied member of the C1Q-TNF-related peptide family. We identified CTRP8 as a ligand of the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1) in glioblastoma multiforme (GBM). The CTRP8-RXFP1 ligand-receptor system protects human GBM cells against the DNA-alkylating damage-inducing temozolomide (TMZ), the drug of choice for the treatment of patients with GBM. The DNA protective role of CTRP8 was dependent on a functional RXFP1-STAT3 signaling cascade and targeted the monofunctional glycosylase N-methylpurine DNA glycosylase (MPG) for more efficient base excision repair of TMZ-induced DNA-damaged sites. CTRP8 also improved the survival of GBM cells by upregulating anti-apoptotic BCl-2 and BCL-XL. Here, we have identified Janus-activated kinase 3 (JAK3) as a novel member of a novel CTRP8-RXFP1-JAK3-STAT3 signaling cascade that caused an increase in cellular protein content and activity of the small Rho GTPase Cdc42. This is associated with significant F-actin remodeling and increased GBM motility. Cdc42 was critically important for the upregulation of the actin nucleation complex N-Wiskott-Aldrich syndrome protein/Arp3/4 and actin elongation factor profilin-1. The activation of the RXFP1-JAK3-STAT3-Cdc42 axis by both RXFP1 agonists, CTRP8 and relaxin-2, caused extensive filopodia formation. This coincided with enhanced activity of ezrin, a key factor in tethering F-actin to the plasma membrane, and inhibition of the actin filament severing activity of cofilin. The F-actin remodeling and pro-migratory activities promoted by the novel RXFP1-JAK3-STAT3-Cdc42 axis were blocked by JAK3 inhibitor tofacitinib and STAT3 inhibitor STAT3 inhibitor VI. This provides a new rationale for the design of JAK3 and STAT3 inhibitors with better brain permeability for clinical treatment of the pervasive brain invasiveness of GBM.

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Suppression of relaxin receptor RXFP1 decreases prostate cancer growth and metastasis

Cited by 74 publications

References 45 publications

Emerging Roles of Angiopoietin-like 4 in Human Cancer

Emerging Roles of Angiopoietin-like 4 in Human Cancer

Expression of LDL-A module of relaxin receptor in prostate cancer cells inhibits tumorigenesis

Novel CTRP8‐RXFP1‐JAK3‐STAT3 axis promotes Cdc42‐dependent actin remodeling for enhanced filopodia formation and motility in human glioblastoma cells

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