Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells

Yang, Xinlei; Chen, M.-W.; Terry, Stéphane; Vacherot, Francis; Bemis, Debra L.; Capodice, Jillian L.; Kitajewski, Jan; Taille, Alexandre de la; Benson, Mitchell C.; Guo, Yinglu; Buttyan, Ralph

doi:10.1038/sj.onc.1209366

Cited by 105 publications

(100 citation statements)

References 31 publications

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“…It is therefore possible that activation of AKT may inhibit AR signaling, leading to NED. Consistent with this hypothesis, it has been shown that WNT signaling suppresses AR protein level (48) and induces NED in LNCaP cells (49). Similarly, HB-EGF, a ligand of the EGF receptor, can inhibit AR signaling (50) as well as inducing NED in LNCaP cells (29).…”

Section: Discussionsupporting

confidence: 51%

Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer

Huang

2007

Journal of Biological Chemistry

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Hormonal therapy of prostate cancer, by inhibiting androgen production and/or androgen function, is the treatment of choice for advanced prostate cancer. Although most patients respond initially, the effect is only temporary, and the tumor cells will resume proliferation in an androgen-deprived environment. The mechanism for androgen-independent proliferation of cancer cells is unclear. Hormonal therapy induces neuroendocrine differentiation of prostate cancer cells, which is hypothesized to contribute to tumor recurrence by a paracrine mechanism. We studied signal transduction pathways of neuroendocrine differentiation in LNCaP cells after androgen withdrawal, and we showed that both the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway and ERK are activated, but only the former is required for neuroendocrine differentiation. A constitutively active AKT promotes neuroendocrine differentiation and a dominant negative AKT inhibits it. Activation of AKT by IGF-1 leads to neuroendocrine differentiation, and neuroendocrine differentiation induced by epinephrine requires AKT activation. We also show that the AKT pathway is likely responsible for neuroendocrine differentiation in DU145, an androgen-independent prostate cancer cell line. Therefore, our study demonstrated a novel function of the AKT pathway in prostate cancer progression and identified potential targets that may be explored for the treatment of androgen-independent cancer.

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Section: Discussionsupporting

confidence: 51%

Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer

Huang

2007

Journal of Biological Chemistry

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“…23,24 Beta-catenin, a component of the Wnt signaling pathway, induces NED when overexpressed in LNCaP cells 24 and blockade of b-catenin signaling suppresses prostate carcinogenesis in TRAMP mice and tumorigenicity of prostate cancer cells in vivo. 25,26 Since the reduction of AR expression is consistent with the evidence that Wnt signaling increases Akt phosphorylation that in turn promotes AR degradation through a proteosomal pathway, 27 we determined the expression levels of b-catenin in our TRAMP specimens. We found high levels of b-catenin in NE samples (Fig.…”

Section: B-catenin Signaling Is Activated During Neuroendocrine Diffementioning

confidence: 94%

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Ciarlo

Benelli

Barbieri

et al. 2011

Intl Journal of Cancer

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Current diagnostic tools cannot predict clinical failure and androgen-independent disease progression for patients with prostate cancer (PC). The survival signaling pathways of prostate cells play a central role in the progression of tumors to a neuroendocrine (NE) phenotype. NE cells demonstrate attributes that suggest that they are an integral part of the signaling cascade leading to castration-resistant PC. In this study, making use of in vitro neuroendocrine differentiation (NED) of human LNCaP and mouse TRAMP-C2 cells after androgen withdrawal, and of the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we characterized a sequence of molecular events leading to NED and identified a number of markers that could be detectable by routine analyses not only in castration resistant PC but also in hormone naïve PC at the time of initial diagnosis. We found that NED associates with AKT activation that in turn regulates heterogeneous nuclear ribonucleoprotein K (hnRNP K), androgen receptor (AR) and b-catenin levels. Addition of molecules targeting membrane-bound receptors and protein kinases blocks NE differentiation in LNCaP and TRAMP-C2 cells. The extent of AKT phosphorylation and hnRNP K, AR and b-catenin levels may have a potential value as prognostic indicators discriminating between androgen-responsive and unresponsive cells and could be used as molecular targets to monitor the anti-tumor action of new therapeutic protocols based on antireceptor agents and/or neuroendocrine hormone antagonists.PC is one of the most common malignancies among males in the western world and a major health problem in many industrialized countries. PC develops and progresses under the influence of androgenic steroids. This influence is consistent with the use of androgen depletion therapies to treat patients with advanced disease.1 However, most patients finally relapse with hormone-refractory prostate cancer and available treatment options are only palliative. Therefore, an understanding of what drives progression to androgen independence is critical. The prostate is known to be dependent not only on androgens but also on growth factors and neuropeptides secreted by NE cells that maintain normal prostate function and play a role in the development of pathological conditions.2 Adult prostate gland possesses basal (proliferating) cells, secretory (luminal) cells and the less abundant (<0.1%) NE cells. Approximately 10% of prostatic carcinoma reveals extensive and multifocal NE features and the presence of NE markers is usually associated with poor prognosis. 3,4 Interestingly, along with the androgen-independent status, an increase in the number of NE cells has been reported in some studies and long-term androgen ablation therapy tends to select prostate tumor populations that are enriched in NE cells.5 These cells lack nuclear androgen receptor 6 ; thus they represent an androgen-insensitive cell phenotype in the prostate and it has been hypothesized that NE cells can lead to the development and growth of androgen-refract...

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“…It was also reported recently that the AR gene is a direct target of LEF-1/TCF. (94) Whereas AR was highly upregulated on the mRNA level by activation of the Wnt pathway in prostate cancer cells, there was a net downregulation of AR protein indicating the involvement of posttranscriptional regulatory mechanisms.…”

Section: Wnt Signalingmentioning

confidence: 98%

“…(96) Taken together, these results suggest that the Wnt signaling pathway modulates AR levels in the prostate cancer cell through a ubiquitin-mediated degradation process controlled by Akt/PKB signaling. (94) In contrast, GSK-3b, which degrades b-catenin, can suppress AR transcriptional activity. (93) Conclusions It has long been recognized that androgens play an important role in prostate carcinogenesis; the disease then progresses to an androgen-independent phenotype when there is no effective therapy.…”

Section: Wnt Signalingmentioning

confidence: 99%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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SummaryProstate cancer is the most frequently diagnosed nonskin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, ''androgen-independent'' tumors in the presence of very low levels of androgens. This review focuses on AR function and AR-target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. IntroductionProstate adenocarcinoma is the most frequently diagnosed non-cutaneous male malignancy and the third leading cause of cancer-related death in men in most western industrialized countries. (1) It is estimated that around 660,000 men worldwide will be diagnosed with prostate cancer and 250,000 men will die from it in 2010; thus, it will remain a major health problem in the future. (1) It was more than 60 years ago that the important role of male sex hormones (androgens) for the development and growth of prostate cancer was demonstrated. (2) Accordingly, androgen ablation therapy has been the main line of therapy for prostate cancer. Therefore, much of the focus in prostate cancer research to date has naturally been on androgens, how to decrease the androgens in the circulation and how to inhibit the androgen receptor (AR).In addition to AR signaling, it has now become evident that other signaling pathways, as well as non-genomic and genomic alterations, are involved in prostate cancer development and progression. Furthermore, recent studies indicated that signaling through AR has a critical role even after androgen ablation and disease progression (for review see Ref.3). In the following sections, we give an overview of androgen signaling in prostate cancer, with a special focus on recent findings about AR function and AR target genes. We then review the involvement of other central signaling pathways in prostate cancer, with a special focus on their cross-talk with the AR signaling pathway. Clinical implications of these findings and potential directions for future research are also outlined.

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Complex regulation of human androgen receptor expression by Wnt signaling in prostate cancer cells

Cited by 105 publications

References 31 publications

Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer

Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Androgen signaling and its interactions with other signaling pathways in prostate cancer

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