Androgen Receptor Expression in Prostate Cancer Cells Is Suppressed by Activation of Epidermal Growth Factor Receptor and ErbB2

Cai, Changmeng; Portnoy, David C.; Wang, Hongyun; Jiang, Xiaolong; Chen, Shaoyong; Balk, Steven P.

doi:10.1158/0008-5472.can-09-0026

Cited by 45 publications

(46 citation statements)

References 52 publications

(53 reference statements)

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“…20 It has also been reported that the EGFR family modulates AR signaling and contributes androgenindependent tumor progression. [24][25][26][27][28] Expression levels of EGFR family were therefore evaluated as possible targets for NEU3 ( Figure 4d). NEU3 was found to increase EGFR and ERBB2 in mRNA and protein levels together with AR and PSA elevation in LNCaP cells under androgendeficient conditions, although they behaved differently in the presence of DHT.…”

Section: Resultsmentioning

confidence: 99%

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

et al. 2011

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Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non-cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer.

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Section: Resultsmentioning

confidence: 99%

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

et al. 2011

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“…These include IL 6 R, EGFR, TGFbR1 and TGFbR2, IGFR, FGFR, and VEGFR. Cross-talk between tyrosine kinase receptors (TKR) and AR takes place via specific and overlapping pathways (Cai et al, 2009). Furthermore, sensitisation of the androgenic response by multi-functional growth factor signalling pathways is thought to be one of the mechanisms through which AR contributes to the emergence of androgen-independent prostate tumours.…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

2009

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Androgen deprivation therapy reduces prostate cancer (PCa) tumour growth; however, disease relapse often ensues independently of androgen stimulation, producing androgen-refractory tumours with increased invasion, proliferation, and malignancy. Androgens downregulate epidermal growth factor receptor (EGFR) in normal prostate but not in PCa. Thus, loss of EGFR regulation and altered signalling may, in part, explain the transition of prostate tumours from androgen dependent to androgen independent. Studies in animal models, PCa cell lines, and tumour specimens suggest that androgens modulate prostate growth and function through mechanisms that involve 'cross-talk' between androgen receptor (AR) and growth factor receptor signalling pathways. The objective of this review is to discuss the paradoxical relationship between androgen regulation of EGFR in normal prostate and PCa. We reviewed the literature from mid-1980s through 2009 to assess the relationship between androgens and EGFR function in modulating the growth of normal prostate and PCa. Loss of androgen regulation of EGFR in PCa may be responsible for increased tumour growth, invasion, and metastasis, with important implications on the clinical management of PCa. We advance the hypothesis that a molecular switch, responsible for downregulating EGFR expression by androgens in the normal prostate, is either lost or modified in PCa.

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“…Negative regulation of AR gene expression can be mediated by ErbB kinases (26) or the Purα transcriptional repressor (27). Among the remaining known factors, androgen itself plays a complex role in regulating AR levels.…”

Section: Figurementioning

confidence: 99%

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

et al. 2010

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Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes. IntroductionRetinoblastoma (RB; encoded by RB1), a tumor suppressor protein, is a critical negative regulator of tumor development. RB prevents tumorigenesis by suppressing cell cycle progression (1). However, the role of RB in tumor progression is poorly understood, and the clinical importance of RB loss during this process has not been well considered. Here, we identified a clinically relevant function for RB in tumor progression, manifest through control of hormone signaling networks.The function of RB in cell cycle control has been well described (1). Conditions favoring cell cycle arrest induce RB hypophosphorylation and activation. Active RB binds to promoters of genes required for S-phase entry (e.g., CCNA2 and MCM7) and, through association with the SWI/SNF complex and corepressor molecules (e.g., Sin3B), elicits transcriptional corepression. Many RB target genes are positively regulated by activator E2F transcription factors, supporting the current model that RB acts by suppressing E2F-mediated transcriptional activation. Indeed, the minimal transcriptional repression and tumor suppression domain of RB contains the E2F binding motif. E2F-independent functions of RB have been identified (2), but the contribution of these functions to tumor suppression is uncertain. Thus, contemporary views of RB suggest that the protein prevents cell cycle deregulation and tumor development through suppression of activator E2Fs.

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Androgen Receptor Expression in Prostate Cancer Cells Is Suppressed by Activation of Epidermal Growth Factor Receptor and ErbB2

Cited by 45 publications

References 52 publications

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

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