Regulation of global gene expression in the bone marrow microenvironment by androgen: Androgen ablation increases insulin‐like growth factor binding protein‐5 expression

Xu, Chang; Graf, Lynn; Fazli, Ladan; Coleman, Ilsa M.; Mauldin, Denise E.; Li, Danbin; Nelson, Peter S.; Gleave, Martin; Plymate, Stephen R.; Cox, Michael; Torok‐Storb, Beverly; Knudsen, Beatrice S.

doi:10.1002/pros.20655

Cited by 18 publications

(15 citation statements)

References 54 publications

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“…In this instance, the cooperation between c-Src and STAT3 could delay osteoblast differentiation with a positive feedback between IL-6 and c-Src pathways. Consistent with our model, we demonstrated that IL-6 enhances the expression of Igfbp5, which has been described to have important roles in bone physiology and pathology [19][20][21][22] . Interestingly, we found that IGFBP5 directly induced c-Src activation without affecting IGF-1 receptor phosphorylation.…”

Section: Discussionsupporting

confidence: 89%

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

et al. 2012

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Interleukin-6 (IL-6) and c-src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-src stimulates IL-6 expression through the sTAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions.

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Section: Discussionsupporting

confidence: 89%

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

et al. 2012

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“…Bcl-2 is an anti-apoptotic protein and its overexpression has been strongly implicated in the development of castration-resistant PCa (McDonell et al , 1992). IGFBP-5 mRNA and protein are upregulated in response to castration and exogenous IGFBP-5 stimulates the proliferation of immortalized prostate epithelial cells (Xu et al , 2007). Also, overexpression of IGFBP-5 accelerates the proliferation of LNCaP cells in androgen-deprived conditions in a PI3K-dependent manner (Miyake et al , 2000).…”

Section: Discussionmentioning

confidence: 99%

NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation

et al. 2011

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Cancer cell molecular mimicry of stem cells (SC) imbues neoplastic cells with enhanced proliferative and renewal capacities. In support, numerous mediators of SC self-renewal have been evinced to exhibit oncogenic potential. We have recently reported that shRNA-mediated knockdown of the embryonic stem cell (ESC) self-renewal gene NANOG significantly reduced the clonogenic and tumorigenic capabilities of various cancer cells. In this study, we sought to test the potential pro-tumorigenic functions of NANOG, particularly, in prostate cancer (PCa). Using quantitative RT-PCR, we first confirmed that PCa cells expressed NANOG mRNA primarily from the NANOGP8 locus on chromosome 15q14. We then constructed a lentiviral promoter reporter in which the -3.8 kb NANOGP8 genomic fragment was used to drive the expression of green fluorescence protein (GFP). We observed that NANOGP8-GFP+ PCa cells exhibited cancer stem cell (CSC) characteristics such as enhanced clonal growth and tumor regenerative capacity. To further investigate the functions and mechanisms of NANOG in tumorigenesis, we established tetracycline-inducible NANOG overexpressing cancer cell lines, including both prostate (Du145 and LNCaP) and breast (MCF-7) cancer cells. NANOG induction promoted drug-resistance in MCF-7 cells, tumor regeneration in Du145 cells, and, most importantly, castration-resistant tumor development in LNCaP cells. These pro-tumorigenic effects of NANOG were associated with key molecular changes, including an upregulation of molecules such as CXCR4, IGFBP5, CD133 and ALDH1. The present gain-of-function studies, coupled with our recent loss-of-function work, establish the integral role for NANOG in neoplastic processes and shed light on its mechanisms of action.

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“…For instance, insulin-like growth factor-binding protein 5 (IGFBP5) has been shown to induce apoptosis and inhibit tumor growth in breast cancer and osteosarcoma cells (44,45). In contrast, IGFBP5 was found to facilitate the progression of prostate cancer (46). Nevertheless, the reasons for the contradicting functions of IRX1 in different tissue contexts are unclear.…”

Section: Nf-κb Pathway Activation Is Involved In Irx1/cxcl14-induced mentioning

confidence: 99%

IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling

Lu¹,

Song²,

Tang³

et al. 2015

J. Clin. Invest.

111

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Regulation of global gene expression in the bone marrow microenvironment by androgen: Androgen ablation increases insulin‐like growth factor binding protein‐5 expression

Abstract: Androgen suppressive therapy increases IGFBP5 in the BM microenvironment and thereby may facilitate the progression of prostate cancer.

Cited by 18 publications

References 54 publications

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation

IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling

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