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1.
Prostate ; 72(12): 1339-50, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22228025

RESUMO

BACKGROUND: Elevated TGF-ß levels are associated with prostate cancer progression. Although TGF-ß is a tumor suppressor for normal epithelial and early-stage cancer cells, it may act paradoxically as a tumor promoter in more advanced cancers, although its effects are largely cell and context dependent. This study analyzed prostate cancer responses to TGF-ß signaling in an isogenic model of androgen-sensitive and castration-resistant prostate cancer cells. METHODS: Phosphorylation and nuclear translocation of Smad2 and Smad3 were analyzed using immunoblotting. Proliferation and cell cycle responses to TGF-ß1 (5 ng/ml) were assessed using growth assays and flow cytometry for DNA content, as well as Western blot and immunoprecipitation of cell cycle proteins. RESULTS: Both androgen-sensitive (LNCaP) and castration-resistant (C4-2 and C4-2B) prostate cancer cell lines demonstrated TGF-ß1-induced phosphorylation and nuclear translocation of Smad2/3 that was robust in metastatic lines. Smad phosphorylation was completely abrogated with inhibition of ALK-5 kinase activity using the kinase inhibitor, SB-431542. Increased sensitivity to TGF-ß1-mediated growth inhibition was observed in C4-2 and C4-2B cells, as compared to LNCaP cells. This was paralleled with downregulation of Cyclin D and increased association of p15(Ink4b) or p27(Kip) with CDK's. Additionally, TGF-ß1 inhibited motility and invasion of metastatic cell lines. CONCLUSIONS: TGF-ß-mediated suppression of growth and motility is enhanced in metastatic, castration-resistant prostate cancer cells. Enhanced TGF-ß1-induced Smad2 and -3 signaling in prostate cancer cells may correlate with tumor suppressive activity. Therefore, the direct effects of TGF-ß1 on prostate cancer cells post-castration may be anti-tumorigenic and growth-suppressive.


Assuntos
Movimento Celular/fisiologia , Proliferação de Células , Inibidores do Crescimento/fisiologia , Neoplasias da Próstata/patologia , Transdução de Sinais/fisiologia , Proteína Smad2/fisiologia , Proteína Smad3/fisiologia , Fator de Crescimento Transformador beta1/fisiologia , Transporte Ativo do Núcleo Celular/fisiologia , Linhagem Celular Tumoral , Humanos , Masculino , Orquiectomia , Fosforilação/fisiologia , Neoplasias da Próstata/terapia , Regulação para Cima/fisiologia
2.
Am J Transl Res ; 2(2): 200-8, 2010 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-20407609

RESUMO

The insulin-like growth factor (IGF) axis is associated intimately with prostate cancer (PCa) development, growth, survival and metastasis. In particular, increased levels of IGFBP-2 expression are associated with advanced PCa, bone metastasis, and the development of castrate resistant PCa. Previously, we reported that androgen treatment decreased intracellular and extracellular IGFBP-2 in the androgen sensitive (AS) PCa cell line, LNCaP. Nonetheless, the mechanism by which androgen treatment decreases expression of IGFBP-2 is not clear. Since elevated IGFBP-2 is associated with a variety of advanced cancers, including PCa, coupled with the fact that hormone ablation is the customary treatment modality for advanced PCa, a complete understanding of the influence of androgens on IGFBP-2 expression is essential. Androgen treatment initially increased steady state IGFBP-2 mRNA levels in LNCaP cells. Extended androgen treatment on LNCaP resulted in a time-dependent decrease in both steady state IGFBP-2 mRNA and protein. Polysomal mRNA analysis showed no difference in IGFBP-2 association with a given fraction; however, Q-PCR revealed less IGFBP-2 mRNA in each androgen-treated fraction. In addition, there was an overall decrease in polysome mRNA after androgen treatment. Extracellular proteolysis of IGFBP-2 was prevented in the presence of serine protease inhibitors. These data indicate that androgen acts via multiple levels to down-regulate IGFBP-2 in LNCaP PCa cells.

3.
Am J Transl Res ; 1(2): 115-30, 2009 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-19956425

RESUMO

Accumulating evidence indicates that alterations in the IGF axis contribute to the development of chemo- and radio-resistant, advanced-stage cancers. Additionally, they contribute to hormonal insensitivity in adenocarcinomas such as those derived from prostate and breast. The ligands, IGF-I and IGF-II, along with their receptors, IGF-IR and IGF-IIR, have been implicated in a wide range of disease. Activation and subsequent signal transduction through the receptors is attenuated, and/or potentiated, by the interactions of IGF axis ligands, IGF-I/II, with the high affinity IGF-binding proteins 1 to 6 (IGFBP1-6). New evidence indicates that the IGFBPs, irrespective of ligand interactions, correlate with the development and metastatic behavior of several cancers. Increased expression of insulin-like growth factor binding protein 2 (IGFBP-2) is found in advanced cancers of the ovary, breast, stomach, adrenal gland, bladder, CNS, and prostate. Further, IGFBP-2 seemingly has ligand-independent effects that participate in the development and dissemination of advanced cancer cells. As such, IGFBP-2 can assist in the development of the lethal phenotype for some cancers. While several reports have shown an important role for IGFBP-2 in the development of androgen insensitivity and the proliferation of AI PCa cells in vivo, these studies have not tested a role for IGFBP-2 in the metastatic spread of AI PCa cells. Additionally, the mechanism of IGFBP-2 action in these events has not been elucidated. The redundancy and abundance of the IGFBPs have precluded a clear understanding of the means by which IGFBP-2 signals. Components of these signaling pathways, particularly IGFBP-2, are being evaluated currently in clinical trials.

4.
J Cell Physiol ; 213(1): 261-8, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17492783

RESUMO

The identification of molecular determinants involved in the promotion of metastasis and development of androgen insensitive prostate cancer (AI-PCa) is necessary to discriminate aggressive from indolent disease and to identify therapeutic targets for advanced disease. Overexpression of one particular member of the insulin like growth factor (IGF) axis, IGFBP-2, is implicated in the development of AI-PCa and other cancers. Using the LNCaP human PCa progression model, we show that the AI and metastatic prostate cancer cell line C4-2B4 expresses greater amounts of secreted IGFBP-2 than the androgen sensitive (AS), non-metastatic LNCaP progenitor cell line. Further, the ability of androgens to decrease extracellular IGFBP-2 levels is attenuated in the AI and metastatic C4-2 cell line. The ability of androgen to negatively regulate extracellular IGFBP-2 levels was blocked by Casodex in a dose-dependent manner. The mechanism underlying the androgen-induced downregulation of secreted IGFBP-2 appears to involve extracellular proteolysis, resulting in the production of IGFBP-2 fragments lacking the ability to bind IGF-I and IGF-II. As C4-2 cells have an attenuated ability to proteolyze IGFBP-2 in response to androgen and C4-2B4 cells express greater amounts of IGFBP-2, our data implies that the diminished regulation of IGFBP-2 and loss of associated proteolytic fragments play a role in the increased metastatic behavior of these cells in vivo. Furthermore, our results suggest that either increased levels of intact IGFBP-2 or decreased levels of IGFBP-2 proteolytic fragments could serve as a biomarker to monitor for progression to AI-PCa.


Assuntos
Androgênios/farmacologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Endopeptidases/metabolismo , Humanos , Masculino , Neoplasias da Próstata/secundário , Receptores Androgênicos/metabolismo
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