Genes upregulated during castration‐induced rat prostatic apoptosis: cloning and characterization of new cDNAs

Bruyninx, Marc; Ammar, Hayet; Reiter, Eric; Cornet, A; Closset, Jean

doi:10.1046/j.1464-410x.2000.00654.x

Cited by 13 publications

(8 citation statements)

References 49 publications

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“…Multiple genes, including IGFBP-3 (20, 21) are upregulated in the prostate in response to androgen-deprivation; however, many of them (including Clusterin (22), and Bax (23)) have been shown not to be essential to prostatic apoptosis utilizing knockout mouse models. To assess the functional contribution of IGFBP-3 to prostate apoptosis in response to androgen-deprivation we utilized the IGFBP-3 knockout (KO) mouse (17) .…”

Section: Resultsmentioning

confidence: 99%

IGFBP-3 Is a Metastasis Suppression Gene in Prostate Cancer

et al. 2011

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The insulin-like growth factor binding protein IGFBP-3 is a pro-apoptotic and anti-angiogenic protein in prostate cancer (CaP). Epidemiological 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 growth 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 occured 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, non-metastatic 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 of the control animals. Cell lines established from Myc:IGFBP-3KO 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 (EMT). Our findings establish a function for IGFBP-3 in suppressing metastasis in prostate cancer, and they also offer the first reported transgenic model of spontaneous metastatic prostate cancer for studies of this advanced stage of disease.

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Section: Resultsmentioning

confidence: 99%

IGFBP-3 Is a Metastasis Suppression Gene in Prostate Cancer

et al. 2011

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“…Because the imbalance between cell proliferation and cell apoptosis is believed to be a key factor in carcinogenesis, particular attention is given to the alteration of the apoptotic pathway in the progression from pre-neoplastic lesion to prostate cancer (Bruyninx et al, 2000;Xie et al, 2000). Despite large efforts and several candidate genes, there is not yet a definite correlation between mutation or alteration in the expression of genes involved in the apoptotic process with different stages of prostate cancer progression (Bostwick et al, 2000;Moul, 1999).…”

Section: Stanzione Et Almentioning

confidence: 99%

Variations of Proline-Rich Kinase Pyk2 Expression Correlate with Prostate Cancer Progression

Stanzione

Picascia

Chieffi

et al. 2001

Laboratory Investigation

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SUMMARY:Proline-rich kinase 2 (Pyk2), also known as CAK␤ (cell adhesion kinase ␤), is a cytoplasmic tyrosine kinase that is structurally related to focal adhesion kinase. Pyk2 is expressed in different cell types including brain cells, fibroblasts, platelets, and other hemopoietic cells. Pyk2 is rapidly tyrosine phosphorylated in response to diverse extracellular signals acting via different post receptor pathways. We have investigated whether this protein kinase is functionally expressed in normal and neoplastic prostate tissues. In this study, we demonstrate that Pyk2 is expressed only in normal epithelial prostate tissue and in benign prostatic hyperplasia, whereas its expression progressively declines with an increasing grade of malignancy of prostate cancer. (Lab Invest 2001, 81:51-59).

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“…In some tumors, IGFBP-3 promotor activity is silenced (17). In animal models, elevated levels of IGFBP-3 are associated with prostate apoptosis following castration (18,19), as well as prostate tumor -suppressive effects of inositol hexaphosphate (20), grape seed extract (21), silibinin (22), and green tea phenols (23).…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo

Liu

Lee²,

Li³

et al. 2005

Clinical Cancer Research

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We have previously identified the retinoid X receptor-a (RXRa) as an insulin-like growth factor binding protein-3 (IGFBP-3) nuclear binding partner, which is required for IGFBP-3-induced apoptosis. In the current study, we investigated the biological interactions of the RXR ligand, VTP194204 and rhIGFBP-3, in vitro and in vivo. In vitro, IGFBP-3 and VTP194204 individually induced apoptosis, and suppressed cell growth in prostate cancer cell lines in an additive manner. In vivo, LAPC-4 xenograft^bearing severe combined immunodeficiency mice treated daily with saline, IGFBP-3, and/or VTP194204 for 3 weeks showed no effect of individual treatments with IGFBP-3 or VTP194204 on tumor growth. However, the combination of IGFBP-3 and VTP194204 treatments inhibited tumor growth by 50% and induced a significant reduction in serum prostate-specific antigen levels. In terminal nucleotidyl transferase^mediated nick end labeling immunohistochemistry of LAPC-4 xenografts, there was modest induction of apoptosis with either IGFBP-3 or VTP194204 individual treatment, but combination therapy resulted in massive cell death, indicating that IGFBP-3 and VTP194204 have a synergistic effect in preventing tumor growth by apoptosis induction. In summary, this is an initial description of the successful therapeutic use of IGFBP-3 as a cancer therapy in vivo, and shows that combination treatment of IGFBP-3 and RXR ligand has a synergistic effect on apoptosis induction leading to substantial inhibition of prostate cancer xenograft growth. Taken together, these observations suggest that combination therapy with IGFBP-3 and RXR ligands may have therapeutic potential for prostate cancer treatment.The insulin-like growth factor (IGF) system is well recognized to play a critical role in cancer development. In particular, IGF binding proteins (IGFBP) have been proposed to act as growth inhibitory molecules through their IGF inhibitory effects. However, a direct IGF-independent role of IGFBPs, particularly IGFBP-3 in the regulation of apoptosis, has emerged over the last decade (1). A key intracellular role for IGFBP-3 was shown in 2000 with the discovery of the nuclear retinoid X receptor a (RXRa) as a binding partner for IGFBP-3. In that study, IGFBP-3 cotransfections potently and dose-dependently inhibited retinoic acid signaling via retinoic acid response element, but enhanced RXR-specific ligand signaling via the retinoid X response element, supporting a co-activator/repressor role for IGFBP-3 in transcription. In addition, IGFBP-3 had no discernible effects in an RXR knock-out line, indicating that RXR is required for IGFBP-3-induced apoptosis. In both androgen-dependent and -independent prostate cancer cell lines, additive effects of IGFBP-3 and RXR ligand on apoptosis were shown (2).Retinoids (including RXR ligands) are prime candidates for cancer chemoprevention because cancer is characterized by abnormal growth with lack of differentiation, which could be modified by retinoids. The nuclear retinoic acid receptors and RXRs media...

show abstract

Genes upregulated during castration‐induced rat prostatic apoptosis: cloning and characterization of new cDNAs

Cited by 13 publications

References 49 publications

IGFBP-3 Is a Metastasis Suppression Gene in Prostate Cancer

IGFBP-3 Is a Metastasis Suppression Gene in Prostate Cancer

Variations of Proline-Rich Kinase Pyk2 Expression Correlate with Prostate Cancer Progression

Combination Therapy of Insulin-Like Growth Factor Binding Protein-3 and Retinoid X Receptor Ligands Synergize on Prostate Cancer Cell Apoptosis In vitro and In vivo

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