Rapid signalling by androgen receptor in prostate cancer cells

Peterziel, Heike; Mink, Sigrun; Schonert, Annette; Becker, Matthias; Klocker, Helmut; Cato, Andrew C. B.

doi:10.1038/sj.onc.1203032

Cited by 234 publications

(177 citation statements)

References 44 publications

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“…These results therefore indicate that the restoration of expression of androgen-repressed transcripts is a systematic feature of recurrent prostate cancers. This provides unbiased, genomic-level support to the hypothesis that the reactivation of androgen-responsive genes in the absence of a ligand is involved in the growth of androgen-independent tumors (Culig et al, 1994;Gregory et al, 1998;Craft and Sawyers, 1998;Craft et al, 1999;Abreu-Martin et al, 1999;Peterziel et al, 1999). The gene expression pro®les do not indicate at which level of androgen regulation this reactivation takes place and what the speci®c molecular mechanisms may be.…”

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confidence: 71%

Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling

et al. 2001

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Androgen deprivation therapy for advanced prostate cancer is often e ective, but not curative. Molecular pathways mediating the therapeutic response and those contributing to the subsequent hormone-refractory cell growth remain poorly understood. Here, cDNA microarray analysis of human CWR22 prostate cancer xenografts during the course of androgen deprivation therapy revealed distinct global gene expression pro®les in primary, regressing and recurrent tumors. Elucidation of the genes involved in the transition between these states implicated speci®c molecular mechanisms in therapy failure and tumor progression. First, we identi®ed a set of androgen-responsive genes whose expression decreased during the therapy response, but was then systematically restored in the recurrent tumors. In addition, altered expression of genes that encode known targets of rapamycin or that converge on the PI3K/AKT/FRAP pathway was observed in the recurrent tumors. Further suggestion for the involvement of these genes in hormone-refractory prostate cancer came from the observation that cells established from the recurrent xenografts were strongly inhibited in vitro by rapamycin. The results of this functional genomic analysis suggest that the combined e ect of re-expression of androgen-responsive genes as well as the activation of rapamycin-sensitive signaling may drive prostate cancer progression, and contribute to the failure of androgendeprivation therapy. Oncogene (2001) 20, 6718 ± 6723.

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confidence: 71%

Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling

et al. 2001

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“…33 Recent data demonstrate that the AR may interact with membrane proteins that activate signaling pathways such as ERKs and PI3K. 14,16,34 These mechanisms of androgen receptor signaling are believed to represent alternative pathways for stimulation of prostate carcinoma cell growth. Our data demonstrate that in PC3-AR cells the AR colocalizes with the EGFR at the membrane level through an interaction of the 2 proteins as demonstrated by coimmunoprecipitation studies performed in the 2 androgen-sensitive cell lines PC3-AR and LNCaP.…”

Section: Egfr Internalization Is Altered In Pc3-ar Cellsmentioning

confidence: 99%

EGF receptor (EGFR) signaling promoting invasion is disrupted in androgen‐sensitive prostate cancer cells by an interaction between EGFR and androgen receptor (AR)

Bonaccorsi

Carloni

Muratori

et al. 2004

Intl Journal of Cancer

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We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of ␣6␤4 integrin expression. The treatment with androgens further reduced invasion of the cells without modifying ␣6␤4 expression, suggesting an interference with the invasion process by androgens. Here, we investigated EGF-mediated signal transduction processes that lead to invasion in PC3-AR cells. We show that EGF-induced EGFR autotransphosphorylation is reduced in PC3-AR cells compared to PC3 cells transfected only with the vector (PC3-Neo). EGF-stimulated PI3K activity, a key signaling pathway for invasion of these cells, and EGF-PI3K interaction are also decreased in PC3 Key words: prostate cancer; epidermal growth factor receptor; androgen receptor; PI3K; invasionProstate Cancer (PC) is one of the most common cancer and the second leading cause of death in American men. 1 Since prostate cancer cell growth is enhanced by androgens, in the advanced stages of the disease, androgen ablation therapy represents a valuable tool for the treatment of these patients. However the development in most patients after few years of treatment of androgenindependent clones, characterized by higher invasiveness and metastatic properties, has focused attention on the molecular mechanisms that lead to loss of androgen-dependence as well as on the pathways that are regulated by androgens in these cells besides proliferation. Indeed, although androgens are the major stimulus for proliferation of prostate cancer cells, maintenance of androgensensitivity appears to keep a more differentiated and less malignant phenotype of these cells. The ability to produce tumors in nude mice, for instance, is higher in androgen-insensitive cell lines (such as PC3 and DU145) with respect to androgen sensitive (LNCaP). 2 In this light, the role of androgens in the regulation of the pathways involved in invasion and metastasis represents a major task in studies on prostate cancer biology. 3 As a result, some androgen-regulated genes involved in signaling pathways that lead to invasion have been recently identified 4 -6 and their role in decreasing invasion ability of androgen-sensitive prostate cancer cells indicated. Migration and invasion of cancer cells is regulated by multiple pathways that employ various growth factor and their receptors, integrins and cytoskeletal elements. A key role is played by the EGF receptor (EGFR), which, following interaction with the integrin ␣6␤4, promotes cell migration through activation of PI3K and other downstream pathways. 7,8 In a previous study, we demonstrated that the expression of androgen receptor in PC3 cells by transfection with a full-length human androgen receptor expression vector (PC3-AR) determined a decrease in the expression of the integrin ␣6␤4 and in the ability of these cells to invade Matrigel in response to EGF. 6 The treatment with the synthetic androgen R1881 determined a ...

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“…It is puzzling that in certain tumor cells nuclear receptors synergize with MAP kinases, e.g. activating Erk, rather than inhibit the activation (Di Domenico et al, 1996;Peterziel et al, 1999).…”

Section: Inhibition Of Signal Transductionmentioning

confidence: 99%