Phosphorylation/Dephosphorylation of Androgen Receptor as a Determinant of Androgen Agonistic or Antagonistic Activity

Wang, Long G.; Liu, Xiao M.; Kreis, Willi; Budman, Daniel R.

doi:10.1006/bbrc.1999.0655

Cited by 50 publications

(32 citation statements)

References 27 publications

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“…However, a biphasic dose-response curve was observed with maximal expression of luciferase at 100 nM DHT and lower than maximal expression observed at DHT concentrations greater than 100 nM. This dose-response curve is consistent with results obtained by others for the regulation of androgen-dependent protein expression in LNCaP cells in culture [44][45][46] (but see Pang et al 29 ). Western blot analysis indicated that more TRPL protein is expressed under the control of the relatively strong CMV promoter than under the control of the PSAEn/ PSAPr prostate cell-specific promoter construct.…”

Section: Discussionsupporting

confidence: 89%

Expression of Drosophila Ca2+ permeable transient receptor potential-like channel protein in a prostate cancer cell line decreases cell survival

et al. 2003

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The effects of expression of Drosophila melanoga ster Ca 2+ permeable transient receptor potential-like (TRPL) channels, under the control of the cytomegalovirus (CMV) or prostate cell-specific promoters, on cell survival and apoptosis in the androgen-sensitive LNCaP prostate cancer cell line were investigated. A prostate-specific antigen (PSA) promoter construct (designated PSAEn/PSAPr) composed of a 0.6 kb region of the promoter and a 1.45 kb region of the enhancer resulted in androgen-dependent and prostatespecific expression of a luciferase reporter gene in transiently transfected LNCaP cells. Expression of the enhanced green fluorescence protein-TRPL chimeric protein under the control of the CMV promoter was confirmed by Western blot. Whereas the majority of the expressed protein was located in the cytoplasmic space, confocal microscopy with the CD-9 protein as a plasma membrane marker demonstrated that approximately 10% of the expressed TRPL protein was located in a band in the plasma membrane. Using recombinant adenoviruses, expression of the TRPL protein was associated with an increase in both the initial and sustained rates of Ca 2+ inflow. Expression of TRPL under the control of the CMV promoter for 96 hours decreased cell number and increased the number of cells undergoing apoptosis by 23 and 27%, respectively. Apoptosis was inhibited by a caspase-3 inhibitor, Z-DEVD-fmk. It is concluded that, when heterologously expressed in LNCaP cells, the TRPL protein leads to a reduction in cell survival due, in part, to the induction of apoptosis. The effects of TRPL are likely caused by enhanced Na + and Ca 2+ inflow to the cells. This finding suggests a novel approach to modify the growth of prostate cancer cells that fail to undergo apoptosis following androgen ablation therapy.

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Section: Discussionsupporting

confidence: 89%

Expression of Drosophila Ca2+ permeable transient receptor potential-like channel protein in a prostate cancer cell line decreases cell survival

et al. 2003

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“…Therefore, it is conceivable that AR is brought to the proximity of a preformed activation complex for further biochemical interaction via caveolin-1 association. Because AR is a phosphoprotein with dynamic regulation of its phosphorylation status (41,42), many signal pathways regulated through the caveolin complex are also implicated in AR transactivation process, including mitogen-activated protein kinase (43) and epidermal growth factor receptor (44). It is reasonable to predict, although it remains to be proven, that AR-caveolin interaction may facilitate at least part of the AR phosphorylation and/or dephosphorylation process.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-1 Interacts with Androgen Receptor

Lu¹,

Schneider

Zheng³

et al. 2001

Journal of Biological Chemistry

211

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Androgen receptor (AR) belongs to the steroid hormone nuclear receptor superfamily. It functions as an androgen-dependent transcriptional factor that regulates genes for cell proliferation and differentiation. Caveolin is a principal component of caveolae membranes serving as a scaffold protein of many signal transduction pathways. Recent results correlate caveolin-1 expression with androgen sensitivity in murine prostate cancer. Furthermore, immunohistochemical staining of patient specimens suggests that caveolin expression may be an independent predictor of progression of prostate cancer. In this study, we investigate the potential interactions between AR signaling and caveolin-1 and demonstrate that overexpression of caveolin-1 potentiates ligand-dependent AR activation. Conversely, down-regulation of caveolin-1 expression by a caveolin-1 antisense expression construct can downregulate ligand-dependent AR activation. Association between these two molecules is also demonstrated by co-localization of AR with caveolin-rich, low-density membrane fractions isolated by an equilibrium sucrose gradient centrifugation method. Co-immunoprecipitation and glutathione S-transferase fusion protein pulldown experiments demonstrate that interaction between AR and caveolin-1 is an androgen-dependent process, offering further evidence for a physiological role of this interaction. Using a mammalian two-hybrid assay system, we determine that the NH 2 terminus region of caveolin-1 is responsible for the interaction with both the NH 2 -terminal domain and the ligand-binding domain of AR.

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“…This drug exerts an inhibitory effect on prostate cell proliferation by blocking androgen action, as well as on bone formation and spermatogenesis [32][33][34]. Interestingly, flutamide has been reported to behave as an AR agonist in human prostate cancer tissue with an AR gene mutation and in human LNCaP cells [14][15][16]18]. The agonist-like response was observed at the level of prostate specific antigen (PSA) expression or cell growth and has important implications for the treatment of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas PC3 cells are androgen-insensitive and have lost AR expression, LNCaP cells overexpress a mutated AR and represent cells that have adapted the AR pathway to be able to grow and survive in patients treated with hormone therapy [35,36]. It has been reported that flutamide can behave as an agonist on AR phosphorylation (i.e., activation), resulting in increased PSA expression in LNCaP cells [18]. This feature is closely related to our results with the same cell line cultured with CSS (to deprive the cells of androgens, other steroids and, in all likelihood, some growth factors) since flutamide augmented the expression of PKCb1 isoenzyme in contrast as CSS did.…”

Section: Discussionmentioning

confidence: 99%

“…The AR mutation in LNCaP consists of a single nucleotide substitution, resulting in one amino acid change in the ligand-binding domain of the receptor (T877A) [17]. As a consequence of this mutation, the AR is activated in response to unusual ligands such as estrogens and progestagens, as well as antiandrogens [17,18]. Flutamide has also been reported to behave as a weak partial agonist of the wild type AR [15].…”

Section: Introductionmentioning

confidence: 99%

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Effects of the Antiandrogen Flutamide on the Expression of Protein Kinase C Isoenzymes in LNCaP and PC3 Human Prostate Cancer Cells

et al. 2004

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Flutamide is a nonsteroidal antiandrogen that is frequently used for total androgen blockage in the treatment of advanced prostate cancer. We investigated the effect of this antiandrogen on the expression of protein kinase C (PKC) isoenzymes (a, b1, e, f) that are involved in cell growth, apoptosis and neoplastic transformation. Androgen-dependent (LNCaP) and independent (PC3) human prostate cancer cells were cultured in a medium that contained fetal bovine serum (FBS) or charcoal-stripped serum (CSS) and treated with 10 lM flutamide. The expression of PKC isoenzymes and the androgen receptor (AR) were analyzed by Western blot and RT-PCR, respectively. Serum steroids differentially regulate the expression of PKC isoenzymes in LNCaP and PC3 cells. Flutamide up-regulated the expression of a, b1 and f, but not e, PKC isoenzymes in CSS-LNCaP cells. These results were not homogeneously reproduced in the presence of androgens. We observed an opposite effect of flutamide, compared to CSS, on PKCb1 isoform expression in CSS-LNCaP suggesting that this antiandrogen exerts an agonistic effect. In PC3 cells flutamide potentiated the expression of the four PKC isoenzymes in almost all conditions tested (FBS-and CSScultured cells). Such effect of flutamide in PC3 cells is independent of AR since no expression of AR was detected. These results provide new evidence on antagonistic/agonistic responses of prostate cancer cells to antiandrogen drugs that are widely used in therapy and show that flutamide can elicit responses in prostate cancer cells that do not express AR.

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Phosphorylation/Dephosphorylation of Androgen Receptor as a Determinant of Androgen Agonistic or Antagonistic Activity

Cited by 50 publications

References 27 publications

Expression of Drosophila Ca2+ permeable transient receptor potential-like channel protein in a prostate cancer cell line decreases cell survival

Expression of Drosophila Ca2+ permeable transient receptor potential-like channel protein in a prostate cancer cell line decreases cell survival

Caveolin-1 Interacts with Androgen Receptor

Effects of the Antiandrogen Flutamide on the Expression of Protein Kinase C Isoenzymes in LNCaP and PC3 Human Prostate Cancer Cells

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