Intracellular adaptor molecules and AR signalling in the tumour microenvironment

Androgen deprivation therapy is the mainstay for treating advanced prostate cancer. A better understanding in the complexity of the androgen receptor (AR) signalling pathway has highlighted that this form of treatment is not sufficient. Since Huggins and Hodges made their crucial observations on the benefits of castration for prostate cancer, significant progress has been achieved in understanding the importance of the cross-talk between the hormone signalling pathway and the kinase signalling network. We now know that preventing androgen production or ligand binding to the AR does not necessarily mark the end of the road for prostate tumour growth. Emerging evidence suggests that there exists a complex set of compensatory mechanisms which allows growth factors to push the transformed cells into a ‘survival adaptation mode’ within the tumour microenvironment. An increase in autocrine and paracrine cascades of growth factor are the most commonly reported events to correlate with progression of androgen-dependent disease to a disseminated androgen independent state. The mechanism of how growth factors can sustain AR activation when cells are deprived of androgens is unknown. This is due to the lack of information about the critical factors linking the intracellular signalling molecules associated with the downstream AR signalling events triggered by growth factors. The aim of this mini review is to highlight a potentially new insight into how intracellular adaptor molecules activated by growth factors may influence and act as a molecular switch to allow the continuation of AR activity in the presence of therapeutic anti-androgens following chemical or surgical castration.     

雄激素受体信号转导途径及其在前列腺癌发展中的作用

前列腺癌是西方男性发病率最高的癌症之一,在采用雄激素阻断疗法后,大部分患者的病情可得到控制,但经过一段时间又会转变为雄激素非依赖型前列腺癌。雄激素受体(AR)在前列腺细胞中扮演重要的角色,它可调节大量基因的表达。在前列腺癌由雄激素依赖型向雄激素非依赖型的转变过程中,AR及其信号途径通过多种方式发挥作用,AR基因的扩增、AR的突变,以及与共激活子之间作用的改变都可能使细胞获得雄激素非依赖型的生长能力。此外,AR还受到多肽生长因子和细胞因子等的调节,表现激素非依赖型的转录激活活性。AR在前列腺癌中作用的阐明对前列腺癌的诊断与治疗有着重大的意义。     

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR)-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR) suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27^Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.     

Androgen receptor action in hormone-dependent and recurrent prostate cancer

The importance of androgens and androgen receptors (AR) in primary prostate cancer is well established. Metastatic disease is usually treated with some form of androgen ablation, which is effective for a limited amount of time. The role of AR in prostate cancers that recur despite androgen ablation therapy is less certain. Most of these tumors express prostate specific antigen (PSA), an androgen-regulated gene; moreover, AR is generally highly expressed in recurrent prostate cancer. We propose that AR continues to play a role in many of these tumors and that it is not only the levels of AR, ligands, and co-regulators, but also the changes in cell signaling that induce AR action in recurrent prostate cancer. These pathways are, therefore, potential therapeutic targets.     

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

Prostate cancer is the most frequently diagnosed non-skin 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.     

Steroid biosynthesis and prostate cancer

The pathways of androgen biosynthesis in human beings have been studied for decades, and the major pathways and enzymes responsible for testosterone and dihydrotestosterone synthesis are now well described. Minor or alternate pathways, which might contribute substantially to androgen production in specific states, have also emerged. Likewise, the requirement of androgen for prostate formation and growth date back over a half-century, and the dependence of prostate cancer on androgens has been known and exploited for as long. Despite the success of testicular removal or suppression, androgen receptor antagonists, and androgen synthesis inhibitors in the treatment of prostate cancer, the sources of androgen, their routes of synthesis, and the contributions of various routes remain topics of debate, particularly in castration-resistant disease when circulating androgens are very low. Here we review the major pathways of 19-carbon steroid synthesis in the adrenal and gonad, peripheral pathways to active androgens, and recent data charting flux of androgen precursors in prostate cancer. We are far from a unified understanding of androgen generation in prostate cancer, but the similarities and differences from glandular androgen synthesis that have already emerged provide important clues to designing the next generation of treatments for this common and devastating disease.     

The androgen receptor (AR) in syndromes of androgen insensitivity and in prostate cancer

The actions of androgens, principally testosterone and 5alpha-dihydrotestosterone, are mediated by a specific receptor protein, the androgen receptor (AR), which is encoded by a single-copy gene located on the human X-chromosome. This receptor protein is a prototypical member of the nuclear receptor family and modulates a range of processes during embryogenesis and in the adult. During embryogenesis, normal AR function is critical to the development of the male phenotype and defects of the AR cause a range of phenotypic abnormalities of male sexual development. Complete loss of AR function has been traced to a number of distinct types of genetic events, including abnormalities of mRNA splicing, the introduction of premature termination codons, and amino acid substitution mutations. An interesting subset of mutations is that in which the AR is completely undetectable using sensitive immunoassays. In all instances, these functional abnormalities are associated with a phenotype of complete androgen insensitivity (complete testicular feminization). By contrast, partial defects of AR function are almost invariably caused by amino acid substitutions within the DNA- and hormone-binding domains of the receptor protein. Such partial defects of receptor function may be caused by changes in either receptor function or receptor abundance.The alterations of AR function and expression that have been characterized in clinical prostatic cancers and in prostate cancer cell lines differ in several important respects. A number of studies have documented the emergence of considerable heterogeneity of AR expression at early stages in the development of prostate cancer. Despite these early changes of AR expression, a substantial body of information suggests that the AR is expressed in advanced forms of prostate cancer, in some cases as the result of amplification events. While infrequent in localized tumors, mutations of the AR have been identified in a number of advanced prostatic cancers and in some instances appear to alter the ligand specificity of the AR. Finally, it appears that other signaling pathways can act to influence AR function.     

The evolutionary impact of androgen levels on prostate cancer in a multi-scale mathematical model

Background  

Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Most untreated prostate cancers retain some dependence upon the AR and respond, at least transiently, to androgen ablation therapy. However, the relationship between endogenous androgen levels and cancer etiology is unclear. High levels of androgens have traditionally been viewed as driving abnormal proliferation leading to cancer, but it has also been suggested that low levels of androgen could induce selective pressure for abnormal cells. We formulate a mathematical model of androgen regulated prostate growth to study the effects of abnormal androgen levels on selection for pre-malignant phenotypes in early prostate cancer development.     

Androgen receptor: a key molecule in the progression of prostate cancer to hormone independence

Despite earlier detection and recent advances in surgery and radiation, prostate cancer is second only to lung cancer in male cancer deaths in the United States. Hormone therapy in the form of medical or surgical castration remains the mainstay of systemic treatment in prostate cancer. Over the last 15 years with the clinical use of prostate specific antigen (PSA), there has been a shift to using hormone therapy earlier in the disease course and for longer duration. Despite initial favorable response to hormone therapy, over a period of time these tumors will develop androgen‐independence that results in death. The androgen receptor (AR) is central to the initiation and growth of prostate cancer and to its response to hormone therapy. Analyses have shown that AR continues to be expressed in androgen‐independent tumors and AR signaling remains intact as demonstrated by the expression of the AR regulated gene, PSA. Androgen‐independent prostate cancers have demonstrated a variety of AR alterations that are either not found in hormone naïve tumors or found at lower frequency. These changes include AR amplification, AR point mutation, and changes in expression of AR co‐regulatory proteins. These AR changes result in a “super AR” that can respond to lower concentrations of androgens or to a wider variety of agonistic ligands. There is also mounting evidence that AR can be activated in a ligand independent fashion by compounds such as growth factors or cytokines working independently or in combination. These growth factors working through receptor tyrosine kinase pathways may promote AR activation and growth in low androgen environments. The clinical significance of these AR alterations in the development and progression of androgen‐independent prostate cancer remains to be determined. Understanding the changes in AR signaling in the evolution of androgen‐independent prostate cancer will be key to the development of more effective hormone therapy. © 2003 Wiley‐Liss, Inc.     

Hormonal control of androgen receptor function through SIRT1

The NAD-dependent histone deacetylase Sir2 plays a key role in connecting cellular metabolism with gene silencing and aging. The androgen receptor (AR) is a ligand-regulated modular nuclear receptor governing prostate cancer cellular proliferation, differentiation, and apoptosis in response to androgens, including dihydrotestosterone (DHT). Here, SIRT1 antagonists induce endogenous AR expression and enhance DHT-mediated AR expression. SIRT1 binds and deacetylates the AR at a conserved lysine motif. Human SIRT1 (hSIRT1) repression of DHT-induced AR signaling requires the NAD-dependent catalytic function of hSIRT1 and the AR lysine residues deacetylated by SIRT1. SIRT1 inhibited coactivator-induced interactions between the AR amino and carboxyl termini. DHT-induced prostate cancer cellular contact-independent growth is also blocked by SIRT1, providing a direct functional link between the AR, which is a critical determinant of progression of human prostate cancer, and the sirtuins.