Urologic Oncology: Seminars and Original Investigations
Seminar articleOncogenic activation of androgen receptor
Introduction
Prostate cancer (PCA) represents the most frequently diagnosed malignancy of men in the United States. PCA is a hormonally regulated malignancy and AR plays an important role in disease progression. One of the most troubling aspects of PCA progression is the conversion from an androgen-dependent to independent (AI) state, which at present defies any effective treatment. In the majority of end-stage, hormone-refractory (HR) tumors, AR continues to be expressed and appears to be activated by castration levels of androgen and adrenal androgens [1], [2], [3]. Thus, a required step towards solving the clinical problem of prostate cancer androgen independence, becomes one of understanding how AR is inappropriately activated and how to inhibit such aberrant signals.
Section snippets
AR and androgen-independence
AR plays a vital role in the development of male reproductive organs. Genetic defects in AR results in the failure to develop a prostate gland, a notion corroborated by recent AR knockout experiments in mice [4], [5]. In normal development, androgen is primarily required for differentiation functions. By contrast, during the development of PCA, androgen becomes a growth and survival factor for tumor cells. At the early stage of localized and metastatic PCA, proliferation depends on androgen,
Androgen-independent AR activation by non-steroids
AR mediates androgen action by being a transcriptional factor that binds specific DNA sequences and recruits RNA polymerase II and a basal transcriptional complex for efficient transcription of cellular genes. The transcriptional activity of AR is mediated by coregulators (coactivators and corepressors) [6], [7] which, in response to androgen's binding to AR and nuclear translocation, are assembled in a dynamic way at different response elements along the genome. The best recognized
Neuroendocrine differentiation and the development of hormone-refractory PCA
Our interest in neuropeptide and its possible role in HR PCA stems from the well documented observation that increased neuroendocrine cells accompany the development of HR PCA. We first demonstrated that IL-6, a progression factor of HR PCA, induced neuroendocrine differentiation of LNCaP [35], which is now supported by several studies reported in the literature [36], [37], [38], [39]. Others reported that androgen-deprivation and forskolin also induced neuroendocrine differentiation of LNCaP,
Inappropriate activation of AR by neuropeptides
A major effort of our laboratory was directed toward studying of the effect of neuropeptide bombesin (and its human homolog GRP) in the induction of androgen-resistance of prostate cancer cells. Our results [48] showed that GRP/bombesin induces LNCaP growth under androgen-free or low-androgen conditions. It activates Src/Etk/FAK tyrosine kinase complex, effectively translocates AR into the nucleus and activates AR transcription activity. Based on microarray analysis, bombesin was found to
Inappropriate activation of AR by other ligands engaging GPCR
Bombesin engages G-protein coupled receptor and channels its signal through Src/Etk/FAK tyrosine kinase complex [20], [48]. Since many of the neurokines released from neuroendocrine cells are ligands for GPCR, and GPCR activation is associated with HR PCA [56], we decided to study whether the above results can be extended to other GPCR ligands such as IL-8 [53] and Relaxin [57]. We found indeed both ligands are able to aberrantly activate AR and induce androgen-independent growth, via similar
In vivo neuropeptide model
To explore Src as a target, we hypothesized that NE cells are androgen-independent and secrete neuropeptides that further support androgen sensitive cell proliferation in the absence of androgens. We developed an in vitro and in vivo model by stable overexpression of the GRP in LNCaP cells (LNCaP-GRP) through transfection and selection. LNCaP-GRP cells demonstrated androgen- and anchorage-independent growth and enhanced cell motility via Src activation. LNCaP-GRP cells developed orthotopic
Clinical implications
Using a novel and specific Src kinase oral inhibitor AZD0530, we demonstrated inhibition of growth and metastases in vivo. The relationship of Src to FAK appears very important in that there was 100% inhibition of lymph node metastases in AZD0530 treated mice. The inhibition of FAK was through its complex to Src. In clinical samples, Src hyperactivation correlates with aberrant androgen receptor activation of high-grade prostate cancer cells and also androgen-independent disease. Furthermore,
Summary and discussion
In this article, we described the mechanism whereby neuropeptides such as bombesin or GRP activates androgen receptor in an androgen-independent fashion. Although our studies were carried out in charcoal-stripped conditions, our results are directly applicable to castration conditions where a low level of androgen is still present. We and others showed that the effects of neuropeptides and androgen on AR activation are synergistic. Perhaps the most provocative finding of this study is the
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