Ligand Activation of the Androgen Receptor Downregulates E-Cadherin-Mediated Cell Adhesion and Promotes Apoptosis of Prostatic Cancer Cells

Nightingale, Joanna; Chaudhary, Khurram; Abel, Paul; Stubbs, Andrew; Romańska, Hanna; Mitchell, Stephen; Stamp, Gordon; Lalani, El–Nasir

doi:10.1016/s1476-5586(03)80028-3

Cited by 26 publications

(19 citation statements)

References 63 publications

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“…1, were separated onto SDS-PAGE and, after blotting, probed with the anti-EAA1 polyclonal antibody. Nightingale et al 2003, Guierini et al 2005, Hatzoglou et al 2005. Inline with our data, it has recently been shown that transfection of AI PC cell lines with the endocytosis protein REPS2 results in inhibition of EGFR internalization and decrease of related signalling (Oosterhoff et al 2005).…”

Section: Discussionsupporting

confidence: 83%

“…Moreover, it has recently been demonstrated that during PC progression from low grade to high grade and metastatic PC, a selective downregulation of the AR-targeted genes that inhibit proliferation, induce differentiation or mediate apoptosis occurs (Hendriksen et al 2006). Altogether this evidence supports the notion that a correct AR pathway may maintain a more differentiated phenotype of PC, as observed in vitro in androgen-positive PC cell lines (Bonaccorsi et al 2000, 2004a, Cinar et al 2001, Davis et al 2003, Nightingale et al 2003, Guerini et al 2005, Hatzoglou et al 2005 both by regulating genes affecting growth and invasion (Bonaccorsi et al 2000, Hendriksen et al 2006 and by interfering with signal transduction of EGF (Bonaccorsi et al 2004a, Oosterhoff et al 2005; present study).…”

Section: Discussionmentioning

confidence: 76%

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Altered endocytosis of epidermal growth factor receptor in androgen receptor positive prostate cancer cell lines

Bonaccorsi

Nosi²,

Muratori³

et al. 2007

Journal of Molecular Endocrinology

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Although androgens and the androgen receptor (AR) are involved in tumorigenesis of prostate cancer (PC) in initial phases, less clear is the role played in advanced androgen-independent (AI) stages of the disease. Several recent reports indicated that re-expression of AR in PC-derived cell lines determines a less aggressive phenotype of the cells. We have previously demonstrated that re-expression of AR decreases the invasion ability of PC3 cells in vitro by affecting signalling and internalization processes of epidermal growth factor receptor (EGFR). Here, we show that reduced EGFR internalization is also a characteristic of AR positive PC cell lines LNCaP and 22Rv1. Reduced internalization in PC3-AR cells is associated to a defective interaction between the EGFR and two adaptor proteins which mediate the endocytotic process, Grb2 and c-Cbl. As a consequence of such reduced interaction, ubiquitination of the receptor, which is mainly mediated by c-Cbl, is also altered. In addition, we show that internalized EGFR co-localizes with early endosome antigen-1, a marker of clathrin-mediated endocytosis, in PC3-Neo cells but not in AR positive cell lines. Conversely, EGFR maintains co-localization with caveolin-1 after EGF stimulation in PC3-AR cells. These data suggest that expression of AR affects clathrin-mediated endocytosis pathway of EGFR, which, according to recent findings, plays an essential role in the completeness of signalling of the receptor. Taken together, these data emphasize the role of AR in the regulation of EGFR endocytotic trafficking and active signalling in PC cells. In view of the role of EGFR signalling in invasion of carcinoma cells, our data may explain the lower invasive phenotype observed in AR-positive cell lines.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 76%

Altered endocytosis of epidermal growth factor receptor in androgen receptor positive prostate cancer cell lines

Bonaccorsi

Nosi²,

Muratori³

et al. 2007

Journal of Molecular Endocrinology

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“…They are involved in the regulation of the expression of many target genes, which are significant during early stages of fetal folliculogenesis and are critical for reproduction (Nightingale et al 2003). Previously, we demonstrated the presence of ARs in the porcine fetal ovary at different stages of gestation (Burek et al 2007) indicating the possible sites of androgen action.…”

Section: Introductionmentioning

confidence: 76%

Antiandrogen flutamide affects folliculogenesis during fetal development in pigs

Knapczyk-Stwora

Grzesiak²,

Ciereszko³

et al. 2013

Reproduction

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Androgen deficiency during prenatal development may affect the expression of genes involved in the folliculogenesis regulation. In order to study the effect of antiandrogen on fetal ovarian development, pregnant gilts were injected with flutamide (for 7 days, 50 mg/kg body weight per day) or corn oil (control groups) starting on gestation days 43 (GD50), 83 (GD90), or 101 (GD108). The obtained fetal ovaries were fixed for histology and immunohistochemistry or frozen for real-time PCR. Morphological evaluation, TUNEL assay, and expression of selected factors (Ki-67, GATA binding transcription factor 4 (GATA4), E-Cadherin and tumor necrosis factor a (TNFa)) were performed. On GD90 and GD108, ovaries following flutamide administration showed a higher number of egg nests and lower number of follicles than those in respective control groups. An increased mRNA and protein expression of Ki-67 was observed in flutamide-treated groups compared with controls on GD50 and GD108 but decreased expression was found on GD90. In comparison to control groups a higher percentage of TUNEL-positive cells was shown after flutamide exposure on GD50 and GD90 and a lower percentage of apoptotic cells was observed on GD108. These data were consistent with changes in TNF (TNFa) mRNA expression, which increased on GD90 and decreased on GD108. E-cadherin mRNA and protein expression was upregulated on GD50 and downregulated on GD90 and GD108. In conclusion diminished androgen action in porcine fetal ovaries during mid-and late gestation leads to changes in the expression of genes crucial for follicle formation. Consequently, delayed folliculogenesis was observed on GD90 and GD108. It seems however that androgens exhibit diverse biological effects depending on the gestational period.

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“…Whether the activated AR can promote prostate cancer cell migration, still remains unknown. Certain studies have indicated that the activated AR-B can promote prostate cancer cell migration (23,24), although others have shown that androgen derivatives can inhibit this phenomenon (25,26). The AR signal pathway could have diverse effects on the molecules involved in the processes of invasion and metastasis which could lead to positive (the up-regulation of NEP, HSP, DPM3/prostin-1, the down-modulation of the ·6ß4 and ·3ß1 integrins, MMP1, MMP3, MMP7, and ET-1 secretion) and to negative (the upregulation of pro-MMP-2) effects on PC cell invasion.…”

Section: Discussionmentioning

confidence: 99%

Differential expression and function of AR isoforms in prostate cancer

Zeng

Li²,

Sun

et al. 2011

Oncol Rep

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Abstract. The androgen receptor (AR) plays a key role in prostate cancer (PCa). Two isoforms of AR, are AR-A and -B, which differ by a lack of the first 187 amino acids in the NH2-terminal transactivation domain of AR-A. Since little is known about the expression and basic function of the AR-A/B isoforms in prostate cancer, the aim of this study was to analyze this possible association. The AR-A, -B and AR-A/B ratio was determined in the tissues of healthy controls, benign prostate hyperplasia (BPH) and PCa by means of Western blot analysis and immunofluorescence. The elevation of AR-A, and -B, as well as the AR-A/B ratio with regard to Gleason scores, were assessed in prostate cancer compared to BPH and normal prostate. In order to further investigate the role of AR A/B isoform function, we transfected PC3 cells with an AR or AR-A expression vector. The overexpression of AR-A and -B significantly decreased the invasion and proliferation of PC3 cells. However, the overexpression of AR-A further decreased proliferation but accelerated the invasion of PC3 cells compared to AR-B. In conclusion, the elevation of AR-A and -B, and the AR-A/B ratio, is associated with prostate cancer occurrence and progression. Furthermore, AR-A could provide a new potential therapy with regard to the decrease in the invasion and proliferation of prostate cancer cells. Our study provides insight into further understanding the biological role of AR-A in its interaction with AR-B and its impact on PCa clinical treatment.

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Ligand Activation of the Androgen Receptor Downregulates E-Cadherin-Mediated Cell Adhesion and Promotes Apoptosis of Prostatic Cancer Cells

Cited by 26 publications

References 63 publications

Altered endocytosis of epidermal growth factor receptor in androgen receptor positive prostate cancer cell lines

Altered endocytosis of epidermal growth factor receptor in androgen receptor positive prostate cancer cell lines

Antiandrogen flutamide affects folliculogenesis during fetal development in pigs

Differential expression and function of AR isoforms in prostate cancer

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