Maximal androgen withdrawal for prostate cancer therapy: current status and future potential

Leewansangtong, Sunai; Crawford, E. David

doi:10.1677/erc.0.0050325

Cited by 6 publications

(9 citation statements)

References 119 publications

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“…Importantly, however, PRK1 signalling strongly induces AR activity in the presence of the adrenal androgens (Figure 6A). We then tested the anti‐androgen CPA, which is commonly used during androgen ablation therapy to block the effects of androgens (Leewansangtong and Crawford, 1998). As expected, CPA at 10 −5 M only marginally activates the AR (Figure 6B).…”

Section: Resultsmentioning

confidence: 99%

A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer

et al. 2003

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In addition to the classical activation by ligands, nuclear receptor activity is also regulated by ligandindependent signalling. Here, we unravel a novel signal transduction pathway that links the RhoA effector protein kinase C-related kinase PRK1 to the transcriptional activation of the androgen receptor (AR). Stimulation of the PRK signalling cascade results in a ligand-dependent superactivation of AR. We show that AR and PRK1 interact both in vivo and in vitro. The transactivation unit 5 (TAU-5) located in the N-terminus of AR suf®ces for activation by PRK1. Thus, TAU-5 de®nes a novel, signal-inducible transactivation domain. Furthermore, PRK1 promotes a functional complex of AR with the co-activator TIF-2. Importantly, PRK signalling also stimulates AR activity in the presence of adrenal androgens, which are still present in prostate tumour patients subjected to testicular androgen ablation therapy. Moreover, PRK1 activates AR even in the presence of the AR antagonist cyproterone acetate that is used in the clinical management of prostate cancer. Since prostate tumours strongly overexpress PRK1, our data support a model in which AR activity is controlled by PRK signalling. Keywords: androgen receptor/nuclear hormone receptor/ prostate cancer/protein kinase C-related kinase/ transcriptional co-activator IntroductionThe androgen receptor (AR) is a member of the steroid hormone receptor family of ligand-activated transcription factors that regulate diverse biological functions including cell growth and differentiation, development, homeostasis and various organ functions in the adult (Mangelsdorf et al., 1995;Cato and Peterzierl, 1998). The AR shares a common modular structure with other nuclear receptors and is composed of several domains that mediate DNA binding, dimerization, ligand binding and transcriptional activity (Mangelsdorf et al., 1995). The ligand binding domain (LBD) performs a number of functions including transcriptional repression or activation by generating the proper interaction surface for multiple partners, including co-repressors and co-activators (Renaud and Moras, 2000). Like other steroid receptors the AR contains a C-terminal ligand-dependent activation function 2 (AF-2) and an additional N-terminal ligand-independent activation function 1 (AF-1). The AR also harbours a less wellde®ned transcription activation unit termed TAU-5 (Jenster et al., 1995;Jenster, 1999). The TAU-5 is located between amino acids 360 and 528 and is required for full activation of the AR (Jenster et al., 1995;Bevan et al., 1999). However, signals that control TAU-5, and thereby AR activity, are unknown. Recent data show agonistinduced interaction between the N-terminal domain (NTD) and the LBD of the AR, supporting the view that both the AF-1 and the AF-2 are required for transcriptional activation (Ikonen et al., 1997;He et al., 2000). It has been suggested that the ligand-induced conformational changes of the LBD in concert with physical interactions with the NTD render the AR fully active (Ikonen et al., 19...

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Section: Resultsmentioning

confidence: 99%

A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer

et al. 2003

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“…Localized disease can be treated relatively successfully by radical prostatectomy (Catalona and Smith, 1998). In contrast, treatments for metastatic prostate cancer, including androgen ablation, are initially effective, but the majority of patients relapse with androgen independent prostate cancer (Denis, 1998;Leewansangtong and Crawford, 1998). The incidence of prostate cancer and the lack of good, long-term treatments for metastatic disease highlight the need for new chemopreventive and chemotherapeutic treatments.…”

Section: Prostate Cancermentioning

confidence: 99%

“…Androgens-Androgen ablation is often used in the treatment of metastatic prostate cancer; however, patients generally relapse with androgen independent disease (Denis, 1998;Leewansangtong and Crawford, 1998). Because of the importance of androgens in prostate cancer, it is important to elucidate any interactions between androgens and 1,25(OH) 2 D 3 in prostate cancer cells.…”

Section: Role Of Androgens and Growth Factors In 125(oh) 2 D 3 Actionmentioning

confidence: 99%

Vitamin D and Prostate Cancer

Polek

Weigel

2002

Journal of Andrology

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Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among American men. It arises primarily from the epithelial secretory cells of the peripheral prostate gland; generally occurs as a multifocal disease within the prostate gland; and then preferentially metastasizes to lymph nodes, bone, lung, and brain. Localized disease can be treated relatively successfully by radical prostatectomy (Catalona and Smith, 1998). In contrast, treatments for metastatic prostate cancer, including androgen ablation, are initially effective, but the majority of patients relapse with androgen independent prostate cancer (Denis, 1998; Leewansangtong and Crawford, 1998). The incidence of prostate cancer and the lack of good, long-term treatments for metastatic disease highlight the need for new chemopreventive and chemotherapeutic treatments. As discussed below, active vitamin D metabolites and analogs of the active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), are candidates for these treatments. Vitamin DVitamin D is best known for its actions in regulating calcium levels and bone remodeling (reviewed in Brown et al, 1999), but recent studies highlight a role for vitamin D in the growth and differentiation of various cell types. It is synthesized in the epidermis by the conversion of its precursor, 7-dehydrocholesterol, into vitamin D 3 , a reaction catalyzed by the ultraviolet rays of sunlight. Subsequent hydroxylation reactions in the liver and kidney produce 1,25(OH) 2 D 3 (Holick, 1984). Levels of 1,25(OH) 2 D 3 are tightly regulated as excess 1,25(OH) 2 D 3 is inactivated by the enzyme 24-hydroxylase (Horst and Reinhardt, 1997).

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“…The tumor of the prostate is, actually, the most frequent malignancy and the second leading cause of male cancer deaths in the Western countries [1,2]. Prostate cancer is usually androgen-dependent in its early stages [3], when most patients positively respond to the suppression of testosterone secretion and/or action, which is mainly achieved through agonistic analogs of LHRH and antiandrogens, given either alone or in combination [3,4]. In later stages, after a given time of tumor remission, a new phase of growth appears in which surviving cancer cells have lost their androgen dependence.…”

Section: Introductionmentioning

confidence: 99%

Activation of the orphan nuclear receptor ROR? induces growth arrest in androgen-independent DU 145 prostate cancer cells

et al. 2001

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BACKGROUND RORα is a transcription factor which belongs to the family of orphan nuclear receptors. The regulatory functions of this receptor are still poorly understood. However, response elements for RORα are present on the promoter of cell cycle‐related genes suggesting that it might be involved in the control of cell proliferation. In this study, we investigated the expression and the possible function of RORα in a human androgen‐independent prostate cancer cell line (DU 145). The thiazolidinedione‐derivative CGP 52608 has been utilized as the specific ligand and activator of RORα. METHODS The effects of CGP 52608 on DU 145 cell proliferation and cell cycle distribution were analyzed by hemocytometer and by FACS analysis, respectively. The expression of RORα as well as the effects of RORα activation on the expression of cell cycle‐related genes were evaluated by RT‐PCR. To clarify whether RORα activation might affect the proliferation of prostate cancer cells also in vivo, nude mice bearing DU 145 tumor xenografts were treated with CGP 52608 at different doses and the growth of the tumors was followed by caliper measurement. RESULTS RORα is expressed in DU 145 cells and the treatment of the cells with the thiazolidinedione‐derivative CGP 52608 brought about a dose‐dependent and significant decrease of cell proliferation. Ligand‐induced activation of RORα affected cell cycle distribution, inducing an accumulation in the G0/G1 phase and a decrease in the S phase. This effect was accompanied by an increased expression of the cyclin‐dependent kinase inhibitor p21WAF1/CIP1 and a decreased expression of cyclin A. The growth of DU 145 tumors in nude mice was significantly reduced by treatment with CGP 52608. CONCLUSIONS These data indicate that, in androgen‐independent DU 145 prostate cancer cells, activation of the orphan nuclear receptor RORα inhibits cell growth, both in vitro and in vivo. RORα also induces cell cycle arrest, possibly through the modulation of the expression of cell cycle‐related genes. Prostate 46:327–335, 2001. © 2001 Wiley‐Liss, Inc.

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Maximal androgen withdrawal for prostate cancer therapy: current status and future potential

Cited by 6 publications

References 119 publications

A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer

A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer

Vitamin D and Prostate Cancer

Activation of the orphan nuclear receptor ROR? induces growth arrest in androgen-independent DU 145 prostate cancer cells

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