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IGFBP-3 is a metastasis suppression gene in prostate cancer.

ABSTRACT: The insulin-like growth factor binding protein IGFBP-3 is a proapoptotic and antiangiogenic protein in prostate cancer (CaP). Epidemiologic studies suggest that low IGFBP-3 is associated with greater risk of aggressive, metastatic prostate cancers, but in vivo functional data are lacking. Here we show that mice that are genetically deficient in IGFBP-3 exhibit weaker growth of primary prostate tumors but higher incidence of metastatic disease. Prostates in IGFBP-3 knockout mice (IGFBP-3KO mice) failed to undergo apoptosis after castration. Spontaneous prostate tumors did not develop in IGFBP-3KO mice, but splenic lymphomas occurred in 23% of female IGFBP-3KO mice by 80 weeks of age. To assess the effects of IGFBP-3 deficiency on prostate cancer development, we crossed IGFBP-3KO mice with a c-Myc-driven model of CaP that develops slow-growing, nonmetastatic tumors. By 24 weeks of age, well-differentiated prostate cancers were observed in all mice regardless of IGFBP-3 status. However, by 80 weeks of age IGFBP-3KO mice tended to exhibit larger prostate tumors than control mice. More strikingly, lung metastases were observed at this time in 55% of the IGFBP-3KO mice but none in the control animals. Cell lines established from IGFBP-3KO:Myc tumors displayed more aggressive phenotypes in proliferation, invasion, and colony formation assays, relative to control Myc tumor cell lines. In addition, Myc:IGFBP-3KO cells exhibited evidence of epithelial-mesenchymal transition. Our findings established a function for IGFBP-3 in suppressing metastasis in prostate cancer, and they also offered the first reported transgenic model of spontaneous metastatic prostate cancer for studies of this advanced stage of disease.

SUBMITTER: Mehta HH

PROVIDER: S-EPMC3148406 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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IGFBP-3 is a metastasis suppression gene in prostate cancer.

Mehta Hemal H HH Gao Qinglei Q Galet Colette C Paharkova Vladislava V Wan Junxiang J Said Jonathan J Sohn Joanne J JJ Lawson Gregory G Cohen Pinchas P Cobb Laura J LJ Lee Kuk-Wha KW

Cancer research 20110622 15

The insulin-like growth factor binding protein IGFBP-3 is a proapoptotic and antiangiogenic protein in prostate cancer (CaP). Epidemiologic studies suggest that low IGFBP-3 is associated with greater risk of aggressive, metastatic prostate cancers, but in vivo functional data are lacking. Here we show that mice that are genetically deficient in IGFBP-3 exhibit weaker growth of primary prostate tumors but higher incidence of metastatic disease. Prostates in IGFBP-3 knockout mice (IGFBP-3KO mice) ...[more]

PMID: 21697285

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Project description:BackgroundOur previous studies demonstrated that a novel quinazoline derivative, DZ-50, inhibited prostate cancer epithelial cell invasion and survival by targeting insulin-like-growth factor binding protein-3 (IGFBP-3) and mediating epithelial-mesenchymal transition (EMT) conversion to mesenchymal-epithelial transition (MET). This study investigated the therapeutic value of DZ-50 agent in in vitro and in vivo models of advanced prostate cancer and the ability of the compound to overcome resistance to antiandrogen (enzalutamide) in prostate tumors.ApproachLNCaP and LNCaP-enzalutamide resistant human prostate cancer (LNCaP-ER) cells, as well as 22Rv1 and enzalutamide resistant, 22Rv1-ER were used as cell models. The effects of DZ-50 and the antiandrogen, enzalutamide (as single agents or in combination) on cell death, EMT-MET interconversion, and expression of IGFBP3 and the androgen receptor (AR), were examined. The TRAMP mouse model of prostate cancer progression was used as a pre-clinical model. Transgenic mice (20-wks of age) were treated with DZ-50 (100 mg/kg for 2 wks, oral gavage daily) and prostate tumors were subjected to immunohistochemical assessment of apoptosis, cell proliferation, markers of EMT and differentiation and IGFBP-3 and AR expression. A tissue microarray (TMA) was analyzed for expression of IGBP-3, the target of DZ-50 and its association with tumor progression and biochemical recurrence.ResultsWe found that treatment with DZ-50 enhanced the anti-tumor response to the antiandrogen via promoting EMT to MET interconversion, in vitro. This DZ-50-mediated phenotypic reversal to MET leads to prostate tumor re-differentiation in vivo, by targeting nuclear IGFBP-3 expression (without affecting AR). Analysis of human prostate cancer specimens and TCGA patient cohorts revealed that overexpression of IGBP-3 protein correlated with tumor recurrence and poor patient survival.ConclusionsThese findings provide significant new insights into (a) the predictive value of IGFBP-3 in prostate cancer progression and (b) the antitumor action of DZ-50, [in combination or sequencing with enzalutamide] as a novel approach for the treatment of therapeutically resistant prostate cancer.

Project description:BackgroundClinical trials have been conducted to clarify the beneficial effects of VD3 (1α,25-dihydroxy vitamin D3, also known as calcitriol) treatment in prostate cancer. However, the molecular mechanisms underlying these effects are not fully understood. Recent studies on IGFBP-3 have indicated its intracellular functions in cell growth and apoptosis. The aim of this study was to confirm the benefits of low-dose VD3 treatment and clarify the molecular mechanisms underlying these beneficial effects in prostate cancer cells.MethodsThe molecular effects of simultaneous treatment of LNCaP cells and their genetically modified cell lines with low concentration of docetaxel and VD3 were biologically and biochemically analyzed. To further determine the effects of VD3 treatment on IGFBP-3 induction system, cells were temporarily treated with VD3 in combination with a transcriptional inhibitor or protein synthesis inhibitor. Bcl-2 protein and its mRNA behavior were also observed in Igfbp-3 expression-modified LNCaP cells to determine the involvement of IGFBP-3 in the suppression of Bcl-2 by VD3 treatment.ResultsChanges in IGFBP-3 expression levels in LNCaP cells indicated that it mediated the inhibition of cell growth induced by VD3 treatment. IGFBP-3 was also found to be a mediator of the enhanced cytotoxicity of prostate cancer cells to VD3 in combination with the anti-cancer drug. We further identified the distinct property of the IGFBP-3 induction system, wherein temporal VD3 stimulation-induced prolonged IGFBP-3 expression and VD3 treatment-induced increase in IGFBP-3 expression were optimized based on the protein concentration rather than the mRNA concentration. Meanwhile, Bcl-2 expression was down-regulated by VD3 treatment in an IGFBP-3-independent manner.ConclusionThese findings indicate the molecular mechanisms of IGFBP-3 induction stimulated by VD3 and IGFBP-3 independent Bcl-2 suppression by VD3 treatment in prostate cancer cells. The results could prompt a re-evaluation of VD3 usage in therapy for patients with prostate cancer.

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IGFBP-3 is a metastasis suppression gene in prostate cancer.

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IGFBP-3 is a metastasis suppression gene in prostate cancer.

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