Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin D derivatives can modulate proliferation and differentiation of cancer cells. Our main source of Vitamin D is ultraviolet (UV) radiation-induced synthesis in skin following sun exposure. UV measurements show that the ambient annual UV exposures increase by about 50% from north to south in Norway. As judged from the incidence rates of squamous cell carcinoma, the same is true for the average personal UV exposures. Solar ultraviolet B (UVB) (280-320nm) exhibits a strong seasonal variation with a minimum during the winter months. The present work aims at investigating the impact of season of diagnosis and residential region, both influencing the Vitamin D level, on the risk of death from lung cancer in patients diagnosed in Norway. Data on all incident cases of lung cancer between 1964 and 2000 were collected. Risk estimates were calculated as relative risk (RR), with 95% confidence intervals using Cox regression model. The seasonal variation of 25-hydroxyvitamin D was assessed from routine measurements of 15,616 samples performed at The Hormone Laboratory of Aker University Hospital. Our results indicate that season of diagnosis is of prognostic value for lung cancer patients, with a approximately 15% lower case fatality for young male patients diagnosed during autumn versus winter (RR=0.85; 95% CI, -0.73 to 0.99; p=0.04). Residing in a high UV region resulted in a further lowering of the death risk than residing in a low UV region. We propose, in agreement with earlier findings for prostate-, breast- colon cancer and Hodgkins lymphoma, that a high level of sun-induced 25-hydroxyvitamin D can be a prognostic advantage for certain groups of lung cancer patients, notably for young men. Lung cancer has for several decades been the leading cause of cancer-related mortality in men in Norway and during the last two decades, became the second most common cause of cancer-related death in women . There are two main types of lung cancer: small cell lung cancer for which chemotherapy is the primary treatment and non-small cell lung cancer, which in its early stages is treated primarily with surgery. Gender-related differences have been described in the literature with respect to survival after therapy, male gender being a significant independent negative prognostic factor . In Norway the 5 years relative survival for localized tumours is about 30% for females and 20% for males. Calcitriol, which is the most active form of Vitamin D, is involved in key regulatory processes such as proliferation, differentiation and apoptosis in a wide variety of cells . Mechanisms for these actions have been proposed to be the interaction of active Vitamin D derivatives with a specific nuclear receptor (VDR receptor) and/or with membrane targets . In vitro studies, performed with lung cancer cell lines, have shown an inhibitive effect of Vitamin D derivatives on cell-growth and proliferation . Furthermore, animal studies have demonstrated the capability of these compounds to suppress invasion, metastasis and angiogenesis in vivo , suggesting that administration of Vitamin D derivatives may be used as adjuvant therapy for lung cancer. Humans get optimal Vitamin D levels by exposure to sun or artificial ultraviolet B (UVB, 280-320nm) sources , and possibly also by consumption of food rich in this nutrient (fat fish, eggs, margarine, etc.) or of vitamin supplements . Among these sources, solar radiation appears to be the most important one . Thus, the Vitamin D status (assessed by the serum levels of 25-hydroxyvitamin D, calcidiol) exhibits a strong seasonal variation that parallels the seasonal change in the fluence of solar UVB that reaches the ground. During winter, the UVB fluence rate in the Nordic countries (50-71 degrees N) is below the level required for Vitamin D synthesis in skin . The maximal level of calcidiol is reached between the months July and September, and is 20-120% higher than the corresponding winter level . Recently we hypothesised that the seasonal variation of calcidiol might be of prognostic significance for colon-, breast- prostate cancer as well as for Hodgkins lymphoma in Norway. Patients diagnosed during summer and autumn have a better survival after standard treatment than patients diagnosed during the winter season . This might be a consequence of a higher Vitamin D level. An American study investigated the effect of season of surgery and recent Vitamin D intake on the survival of non-small cell lung cancer patients. The authors reported a significant beneficial joint effect of summer season and high Vitamin D intake compared with winter season and low Vitamin D intake while Vitamin D intake alone did not affect prognosis. Similar results were recently reported from a large study in United Kingdom involving over a million cancer patients including over 190,000 patients diagnosed with lung cancer . Norway (58-71 degrees N) has a significant north-south variation in UV fluence. This makes the country suitable for studies relating cancer epidemiology to UV levels . We investigated whether variations in UV, and, consequently, in Vitamin D level, influence the prognosis of lung cancer, using season of diagnosis and residential regions as variables. Survival data obtained for patients diagnosed over a 40 years period were compared with variations in serum Vitamin D levels obtained from routine measurements performed in The Hormone Laboratory of Aker University Hospital during the period 1996-2001. Seasonal and gender variations in Vitamin D level have been estimated from the analyses.
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PMID:Seasonal and geographical variations in lung cancer prognosis in Norway. Does Vitamin D from the sun play a role? 1720 91

The endocrine signaling governing nuclear receptor (NR) function has been known for several decades to play a crucial role in the onset and progression of several tumor types. Notably among these are the estrogen receptor (ER) in breast cancer and androgen receptor (AR) in prostate cancer. Other nuclear receptors may be involved in cancer progression including the peroxisome-proliferator activating receptor gamma (PPARgamma), which has been implicated in breast, thyroid, and colon cancers. These NR are phylogenetically conserved modular transcriptional regulators, which like histones, undergo post-translational modification by acetylation, phosphorylation and ubiquitination. Importantly, the transcriptional activity of the receptors is governed by the coactivator p300, the activity of which is thought to be rate-limiting in the activity of these receptors. Histone acetyltransferases (HATs) and histone deacetylases (HDACs), modify histones by adding or removing an acetyl group from the epsilon amino group of lysines within an evolutionarily conserved lysine motif. Histone acetylation results in changes in chromatin structure in response to specific signals. These enzymes can also directly catalyze the NRs themselves, thus modifying signals at the receptor level. The post-translational modification of NR which is regulated by hormones, alters the NR function toward a growth promoting receptor. The deacetylation of NR is mediated by TSA-sensitive and NAD-dependent deacetylases. The regulation of NR by NAD-dependent enzymes provides a direct link between intracellular metabolism and hormone signaling.
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PMID:The functional significance of nuclear receptor acetylation. 1729 55

The nuclear receptor ERRalpha (estrogen-related receptor alpha) is known to modulate the estrogen-signaling pathway, but the biological significance of ERRalpha in the prostate remains unclear. We investigated the expression of ERRalpha in human prostate tissues and cancer cell lines to evaluate the potential roles of the receptor in prostate cancer (PC). Western blot analysis of ERRalpha was performed in three cell lines of human PC (LNCaP, DU145 and PC-3). The expressions of ERRalpha in cancerous lesions (n = 106) and benign foci (n = 99) of 106 surgically obtained prostate specimens were evaluated by immunohistochemistry. The relationships between the ERRalpha expression and clinicopathological features were evaluated. Western blot analysis using the polyclonal anti-ERRalpha antibody detected a 52 kD band in all three PC cell lines. Positive immunostaining of ERRalpha in the nuclei was found in 73 (69%) cancerous and 47 (47.5%) benign epithelium, whereas the stromal tissues were negative for ERRalpha. The mean immunoreactivity score (IR score) of the cancerous lesions (3.5 +/- 2.6) was significantly higher than that of the benign foci (1.8 +/- 2.1) (p < 0.0001). The IR score of the cancerous lesions significantly correlated with the Gleason score (p = 0.0135). Univariate and multivariate hazard analyses revealed significant correlations between elevated ERRalpha expression and poor cancer-specific survival (p = 0.0141 and 0.0367, respectively). The enhanced expression of ERRalpha might play a role in the development of human PC and serve as a significant prognostic factor for the disease.
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PMID:Increased expression of estrogen-related receptor alpha (ERRalpha) is a negative prognostic predictor in human prostate cancer. 1729 52

In several cases of prostate cancer, resistance to hormonal therapies is observed. Alternative therapeutic strategies for the treatment of prostate cancer are of great interest. Participation of the nuclear receptor PPARgamma in the physiopathology of the prostate, in particular in prostate cancer has been recently studied. PPARgamma is a member of the hormone nuclear receptor superfamily. As for most members of the family, its activity is regulated by ligands. PPARgamma has been shown to be over-expressed in several cancers, including prostate cancer. In vitro and in vivo studies have demonstrated anti-proliferative and pro-apoptotic actions of the PPARgamma agonists thiazolidinediones, suggesting that PPARgamma could be a promising therapeutical target for the treatment of cancer. No effects of PPARgamma agonists have been observed, however, in a large randomized clinical trial in the "rising PSA" group of prostate cancer patients. This suggests that PPARgamma activity is controled by other factors, in addition to its ligands, in prostate cancer. We have shown that PPARgamma activity is repressed by HDACs. Moreover, PPARgamma activity is enhanced in the presence of HDAC inhibitors. A combination treatment using HDAC inhibitors and PPARgamma agonists results in growth arrest of prostate tumors in mice. Furthermore, the combination therapy inhibits invasion of prostate cancer cells in vivo, through upregulation of the expression of the E-cadherin gene.
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PMID:[Role of PPARgamma in the control of prostate cancer growth: a new approach for therapy]. 1733 82

Prostate cancer is a common cause of death in men and remains incurable in the metastatic setting. In 2004, 2 landmark trials using docetaxel-based chemotherapy, TAX 327 and SWOG 99-16, showed a survival benefit for the first time in metastatic, hormone-refractory prostate cancer. Current research suggests that several distinct mechanisms of androgen-refractory disease may converge in patients with disease progression on androgen deprivation therapy. These findings have identified several potential targets for therapeutic intervention. Current standard and investigational treatment options for this disease are discussed, including chemotherapy and rapidly evolving therapies in phase II/III trials involving antiangiogenic therapies, signal transduction inhibitors, immunomodulatory agents, and nuclear receptor targets. In light of a growing array of treatment options and an increasingly chronic natural history, this review supports a multidisciplinary care approach to these patients, including medical oncologists, urologists, and radiation oncologists, to optimize survival and quality of life.
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PMID:Current standard and investigational approaches to the management of hormone-refractory prostate cancer. 1738 72

Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]ethenyl}-1H-tetrazole, 5-{4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorobenzylidene}thiazolidine-2,4-dione, and (3E)-4-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 microM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.
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PMID:An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity. 1748 79

Androgen antagonists or androgen deprivation is a primary therapeutic modality for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which the androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this report, we demonstrate that sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide-dependent histone deacetylase (HDAC) linked to the regulation of longevity, is required for androgen antagonist-mediated transcriptional repression and growth suppression. Androgen antagonist-bound androgen receptor (AR) recruits SIRT1 and nuclear receptor corepressor to AR-responsive promoters and deacetylates histone H3 locally at the prostate-specific antigen promoter. Furthermore, SIRT1 down-regulation by small interfering RNA or by pharmacological means increased the sensitivity of androgen-responsive genes to androgen stimulation, enhanced the sensitivity of prostate cancer cell proliferative responses to androgens, and decreased the sensitivity of prostate cancer cells to androgen antagonists. In this study, we demonstrate the ligand-dependent recruitment of a class III HDAC into a corepressor transcriptional complex and a necessary functional role for a class III HDAC as a transcriptional corepressor in AR antagonist-induced transcriptional repression. Collectively, these findings identify SIRT1 as a corepressor of AR and elucidate a new molecular pathway relevant to prostate cancer growth and approaches to therapy.
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PMID:Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. 1750 61

The androgen receptor (AR) is a nuclear receptor transcription factor that mediates the cellular actions of androgens, the male sex steroids. Androgen-dependent tissues, such as the prostate, rely on androgen action for their development as well as their maintenance in adulthood. This requirement is exploited during systemic therapy of prostate cancer, which is initially an androgen-dependent disease. Indeed, androgen ablation, which prevents the production or blocks the action of androgens, inhibits prostate cancer growth. Invariably, the disease recurs with a phenotype resistant to further hormonal manipulations. However, this so-called androgen depletion-independent prostate cancer remains dependent on a functional AR for growth. Many studies have focused on the mechanistic and structural basis of AR activation with the important goal of understanding how the AR is activated at this stage of the disease. In this review, we summarize how these studies have revealed important functional domains in the AR protein and have provided initial clues to their role in prostate cancer development and progression. A comprehensive understanding of the role and functional relationships between these AR domains could lead to the development of novel AR-directed therapies for prostate cancer.
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PMID:Androgen receptor structural and functional elements: role and regulation in prostate cancer. 1763 35

The mechanisms by which androgen receptor (AR) antagonists inhibit AR activity, and how their antagonist activity may be abrogated in prostate cancer that progresses after androgen deprivation therapy, are not clear. Recent studies show that AR antagonists (including the clinically used drug bicalutamide) can enhance AR recruitment of corepressor proteins [nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid receptors (SMRT)] and that loss of corepressors may enhance agonist activity and be a mechanism of antagonist failure. We first show that the agonist activities of weak androgens and an AR antagonist (cyproterone acetate) are still dependent on the AR NH(2)/COOH-terminal interaction and are enhanced by steroid receptor coactivator (SRC)-1, whereas the bicalutamide-liganded AR did not undergo a detectable NH(2)/COOH-terminal interaction and was not coactivated by SRC-1. However, both the isolated AR NH(2) terminus and the bicalutamide-liganded AR could interact with the SRC-1 glutamine-rich domain that mediates AR NH(2)-terminal binding. To determine whether bicalutamide agonist activity was being suppressed by NCoR recruitment, we used small interfering RNA to deplete NCoR in CV1 cells and both NCoR and SMRT in LNCaP prostate cancer cells. Depletion of these corepressors enhanced dihydrotestosterone-stimulated AR activity on a reporter gene and on the endogenous AR-regulated PSA gene in LNCaP cells but did not reveal any detectable bicalutamide agonist activity. Taken together, these results indicate that bicalutamide lacks agonist activity and functions as an AR antagonist due to ineffective recruitment of coactivator proteins and that enhanced coactivator recruitment, rather than loss of corepressors, may be a mechanism contributing to bicalutamide resistance.
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PMID:Activity of androgen receptor antagonist bicalutamide in prostate cancer cells is independent of NCoR and SMRT corepressors. 1780 55

Brassinosteroids (BRs) are steroid plant hormones that are essential for many plant growth and developmental processes, including cell expansion, vascular differentiation and stress responses. Up to now the inhibitory effects of BRs on cell division of mammalian cells are unknown. To determine basic anticancer structure-activity relationships of natural BRs on human cells, several normal and cancer cell lines have been used. Several of the tested BRs were found to have high cytotoxic activity. Therefore, in our next series of experiments, we tested the effects of the most promising and readily available BR analogues with interesting anticancer properties, 28-homocastasterone (1) and 24-epibrassinolide (2), on the viability, proliferation, and cycling of hormone-sensitive/insensitive (MCF-7/MDA-MB-468) breast and (LNCaP/DU-145) prostate cancer cell lines to determine whether the discovered cytotoxic activity of BRs could be, at least partially, related to brassinosteroid-nuclear receptor interactions. Both BRs inhibited cell growth in a dose-dependent manner in the cancer cell lines. Flow cytometry analysis showed that BR treatment arrested MCF-7, MDA-MB-468 and LNCaP cells in G(1) phase of the cell cycle and induced apoptosis in MDA-MB-468, LNCaP, and slightly in the DU-145 cells. Our results provide the first evidence that natural BRs can inhibit the growth, at micromolar concentrations, of several human cancer cell lines without affecting the growth of normal cells. Therefore, these plant hormones are promising leads for potential anticancer drugs.
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PMID:Anticancer and antiproliferative activity of natural brassinosteroids. 1786 17


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