Activation of the Androgen Receptor N-terminal Domain by Interleukin-6 via MAPK and STAT3 Signal Transduction Pathways

Ueda, Takeshi; Bruchovsky, Nicholas; Sadar, Marianne D.

doi:10.1074/jbc.m108255200

Cited by 348 publications

(359 citation statements)

References 76 publications

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“…Thus, ZIPK might contribute to anti-apoptotic and proliferative functions of AR and provide a growth advantage to cancer cells. Third, two other interaction partners of ZIPK, namely Par-4 (Page et al, 1999a) and STAT3 (Sato et al, 2005), are also linked to the AR (Ueda et al, 2002;Gao et al, 2006). It will be interesting to elucidate a possible network in which ZIPK cooperates with different co-activators to activate distinct sets of AR target genes.…”

Section: Discussionmentioning

confidence: 99%

ZIP kinase plays a crucial role in androgen receptor-mediated transcription

et al. 2007

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The androgen receptor (AR) is a ligand-dependent transcription factor that plays a crucial role in the development and homeostasis of the prostate and in prostate cancer. The transcriptional activity of AR is mediated by interaction with multiple co-activators, which serve in chromatin modification or remodeling, or provide a link between specific and general transcription factors. We have identified zipper interacting protein (ZIP) kinase as a novel transcriptional co-activator of the AR. ZIP kinase enhanced expression of AR-responsive promotor/ luciferase reporter constructs in a hormone-and kinasedependent manner. Similar results were obtained for glucocorticoid receptor but not for progesterone receptor and estrogen receptor. Following hormone treatment, AR and ZIP kinase formed physical complexes and associated with the promoter and enhancer of the prostate-specific antigen gene, as revealed by chromatin immunoprecipitation. Strikingly, depletion of ZIP kinase by siRNA led to significant reduction of AR-mediated transactivation. The interaction of ZIP kinase with AR seems to be mediated in part by apoptosis antagonizing transcription factor and in part by direct binding. Interestingly, AR was not phosphorylated by ZIP kinase in vitro, suggesting that it phosphorylates other co-activators or chromatin proteins.

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Section: Discussionmentioning

confidence: 99%

ZIP kinase plays a crucial role in androgen receptor-mediated transcription

et al. 2007

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“…(42) The role of some of these growth factors, such as EGF and IGF, is controversial since there were also reports that failed to demonstrate ligand-independent activation by these agents. (43,44) The basis of these differences is not clear at present, but could be due to cell-and promoter-specific effects of these growth factors or may be related to the methodological issues in these studies. Nevertheless, the data in favor of the involvement of growth factor signaling in prostate carcinogenesis are compelling and there is a need to define the critical molecular events leading to activation of AR in vivo by these androgen-independent pathways.…”

Section: Tmprss2mentioning

confidence: 99%

“…(86) A number of studies have implicated crosstalk between IL-6 and AR signaling. (43,88,89) IL-6 has been shown to activate AR in a ligand-independent and synergistic manner. (89) In addition, IL-6 induced expression of PSA in androgen-dependent LNCaP cells and this was mediated through upregulation of AR gene expression.…”

Section: Il-6 Signalingmentioning

confidence: 99%

“…(90) In addition to MAPK, activated STAT3 (signal transducer and activator of transcription 3) has been implicated as an important signaling molecule for IL-6 to activate AR in both androgen-dependent and -independent cell lines. (43,88,91) In contrast to androgen responsive cells, it has been suggested that inhibition of the PI3K/Akt pathway induced AR reporter activity in the presence of IL-6 in the androgen-independent cell lines PC-3 and DU145. (88) In addition, mTor, a downstream target of Akt, has been shown to inhibit AR levels or activity mediated by Erb1 in LNCaP cells.…”

Section: Il-6 Signalingmentioning

confidence: 99%

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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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“…This mechanism is supported by data that demonstrate IL-6 can activate the AR in a ligand-independent manner (Ueda et al, 2002;Corcoran and Costello, 2003). Evidence in clinical tissue to support these in vitro observations are sparse, although it is reported that IL-6 receptor expression is eightfold higher in prostate cancer tissue compared to normal tissue (Giri et al, 2001) and that phosphorylated STAT3 is observed in 82% of human prostate tumours and expression levels correlate with Gleason score (Barton et al, 2004).…”

mentioning

confidence: 92%

Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer

et al. 2007

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The main cause of prostate cancer-related mortality is the development of hormone-refractory disease. Circulating serum levels of IL-6 are raised in hormone-refractory prostate cancer patients and evidence from cell line studies suggests that the IL-6R/JAK/STAT3 pathway may be involved in development of this disease. In the current study we investigate if expression levels of these family members are implicated in the development of hormone-refractory prostate cancer. Immunohistochemistry using IL-6R, JAK1, STAT3, pSTAT3 Tyr705 and pSTAT3 Ser727 antibodies was performed on 50 matched hormone-sensitive and hormone-refractory tumours pairs. An increase in expression of cytoplasmic IL-6 receptor, with the development of hormone-refractory prostate cancer was associated with reduced time to relapse (P ¼ 0.0074) while an increase in expression of cytoplasmic pSTAT3 Tyr705 was associated with reduced patient survival (P ¼ 0.0003). In addition, those patients with high expression of cytoplasmic pSTAT3 Tyr705 in their hormone-refractory tumours had significantly shorter time to death from biochemical relapse and overall survival in comparison to those patients with low expression of cytoplasmic pSTAT3 Tyr705 (P ¼ 0.002 and P ¼ 0.0027, respectively). Activation of STAT3, via phosphorylation is associated with reduced patient survival, suggesting that activation of the IL-6R/JAK/STAT3 pathway is involved with development of hormone-refractory prostate cancer.

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Activation of the Androgen Receptor N-terminal Domain by Interleukin-6 via MAPK and STAT3 Signal Transduction Pathways

Cited by 348 publications

References 76 publications

ZIP kinase plays a crucial role in androgen receptor-mediated transcription

ZIP kinase plays a crucial role in androgen receptor-mediated transcription

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

Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer

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