Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Although the progression of prostate cancer initially is dependent on androgens, tumor progression to an androgen-independent growth eventually occurs in most of patients treated with androgen ablation and/or antiandrogen therapy. After the initial response, antiandrogens lose their efficacy and eventually act as agonists to promote androgen receptor (AR)-mediated growth of prostate cancer cells. An aberrant regulation of AR activity, presumably by AR coregulators, may contribute to this acquired agonist activity of antiandrogens. Using an in vitro mutagenesis and a double-negative selection in yeast two-hybrid screening, we have identified a dominant-negative AR coregulator ARA70 (dARA70N), which can inhibit AR transcriptional activity by inactivating the normal function of ARA70 in the LNCaP cells. Whereas ARA70 in oligomeric form interacts with AR and enhances its transcriptional activity, dARA70N lacks AR interaction and might retain the ability to form a non-functional heteromer with ARA70 and interrupt AR transcriptional activity without a change in AR protein itself. The addition of dARA70N reduces the agonist activity and rescues the normal function of antiandrogens in prostate cancer cells. RNA-interference-mediated silencing of ARA70 gene further confirms these observations. Taken together, these findings indicate that ARA70 may contribute to the acquired agonist activity of antiandrogens and plays an important role in making prostate cancer cells resistant to androgen ablation and/or antiandrogen therapy. ARA70 may, thus, be a critical target for developing therapeutic agents against AR-mediated progression of prostate cancer.
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PMID:Reducing the agonist activity of antiandrogens by a dominant-negative androgen receptor coregulator ARA70 in prostate cancer cells. 1264 93

In an effort to understand transcriptional regulation by the peroxisome proliferator-activated receptor alpha (PPARalpha), we investigated the ability of a number of transcriptional coactivators to enhance PPARalpha:retinoic acid receptor (RXR) mediated transcription. We identified ARA70, a coactivator of the androgen receptor and PPARgamma, as a ligand-enhanced coactivator of PPARalpha in the prostate cancer cell line DU145. In prostate cancer cells, ARA70 demonstrated the strongest enhancement of PPARalpha transcription among the coactivators examined. Mutation of the N-terminal of the PPARalpha ligandbinding domain dramatically reduced the ability of ARA70 to enhance PPARalpha:RXR transcription. ARA70 was able to physically interact with both the wild-type and mutant PPARalpha as determined by coimmunoprecipitation. However, in the adrenal cell line Y1, ARA70 behaved as a repressor of PPARalpha while still able to coactivate PPARgamma.
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PMID:Induction and repression of peroxisome proliferator-activated receptor alpha transcription by coregulator ARA70. 1289 77

Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR's association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.
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PMID:The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor. 1474 96

Human androgen receptor (AR) associates with coactivator or corepressor proteins that modulate its activation in the presence of ligand. Early studies on AR coactivators in carcinoma of the prostate were hampered because of lack of respective antibodies. Investigations at mRNA level revealed that most benign and malignant prostate cells express common coactivators. AR coactivators SRC-1 and TIF-2 are up-regulated in tissue specimens obtained from patients who failed prostate cancer endocrine therapy. Increased expression of these coactivators is associated with enhanced activation of the AR by the adrenal androgen dehydroepiandrosterone. Similar association between AR coactivator expression and high prostate cancer grade and stage was reported for RAC-3 (SRC-3). The transcriptional integrator CBP was detected in clinical specimens representing organ-confined prostate cancer, lymph node metastases and tumour cell lines. Agonistic effect of the nonsteroidal antiandrogen hydroxyflutamide was strongly potentiated in prostate cells transfected with CBP cDNA. A functional homologue of CBP, p300, is implicated in ligand-independent AR activation by interleukin-6. The AR coactivator Tip60, which is up-regulated by androgen ablation, is recruited to the promoter of the prostate-specific antigen gene in the absence of androgen in androgen-independent prostate cancer sublines. It was proposed that the cofactor ARA70 is a specific enhancer of AR action. However, research from other laboratories has demonstrated interaction between ARA70 and other steroid receptors. Although in some cases dominant-negative coactivator mutants inhibited proliferation of prostate cancer cells in vitro, confirmation from in vivo tumour models is missing. In summary, several abnormalities in AR coactivator expression and function are associated with prostate cancer progression.
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PMID:Expression and function of androgen receptor coactivators in prostate cancer. 1566 89

Prostate cancer is the most commonly diagnosed noncutaneous neoplasm and second most common cause of cancer-related mortality in western men. To investigate the mechanisms of prostate cancer development and progression, we did expression profiling of human prostate cancer and benign tissues. We show that the SOX4 is overexpressed in prostate tumor samples compared with benign tissues by microarray analysis, real-time PCR, and immunohistochemistry. We also show that SOX4 expression is highly correlated with Gleason score at the mRNA and protein level using tissue microarrays. Genes affected by SOX4 expression were also identified, including BCL10, CSF1, and NcoA4/ARA70. TLE-1 and BBC3/PUMA were identified as direct targets of SOX4. Silencing of SOX4 by small interfering RNA transfection induced apoptosis of prostate cancer cells, suggesting that SOX4 could be a therapeutic target for prostate cancer. Stable transfection of SOX4 into nontransformed prostate cells enabled colony formation in soft agar, suggesting that, in the proper cellular context, SOX4 can be a transforming oncogene.
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PMID:Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. 1661 20

ARA70 is a coactivator of androgen receptor (AR), a ligand-dependent transcription factor that plays an important role in prostate cancer. There are 2 variants of ARA70, the full length 70 kd ARA70alpha isoform and the internally spliced 35 kd ARA70beta isoform. Recent studies have suggested different expression and roles of the 2 isoforms in several endocrine malignancies, including prostate, breast, and ovarian cancers. To study the roles of these isoforms in cancers, we produced isoform-specific polyclonal antibodies. The anti-ARA70alpha antibody was raised in rabbits against 326 amino acid peptide corresponding to the internal deletion missing from ARA70beta (ARA70id), whereas the anti-ARA70beta antibody was raised against 18 amino acid polypeptide spanning the splice junction, with Gln-Gln motif unique to ARA70beta. The antisera were affinity purified on CNBr-activated sepharose 4B, and their specificity tested against bacterially expressed, Ni-column-purified ARA70alpha, ARA70beta, and ARA70id. The anti-ARA70alpha antibody recognized ARA70alpha and ARA70id, but not ARA70beta. The anti-ARA70beta antibody was specific to ARA70beta and did not cross-react with ARA70alpha or ARA70id. We then used these antibodies to detect ARA70 isoforms in crude extracts made of prostate cancer cell lines and performed immunohistochemical localization of these proteins in prostate tissues. ARA70beta localized to the cytosol, whereas ARA70alpha was found in the nucleus, supporting the notion of their dissimilar functions.
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PMID:Androgen receptor coactivator ARA70alpha and ARA70beta isoform-specific antibodies: new tools for studies of expression and immunohistochemical localization. 1809 27

ARA70 was first identified as a gene fused to the ret oncogene in thyroid carcinoma and subsequently as a co-activator for androgen receptor (AR). Two isoforms of ARA70 have been identified: a 70-kDa version called ARA70 alpha and an internally spliced 35-kDa variant termed ARA70 beta. We have previously reported that ARA70 alpha expression is reduced in prostate cancer, and its overexpression inhibits proliferation of LNCaP prostate cancer cells. However, the function of the ARA70 beta isoform in prostate cancer is not understood. In this report we examined the effects of ARA70 beta on AR transcriptional regulation as well as prostate cancer cellular proliferation and invasion. Although both ARA70 alpha and ARA70 beta functioned as transcriptional co-activators of AR in cell-based reporter assays, ARA70 beta overexpression, in contrast to ARA70 alpha, promoted prostate cancer cellular proliferation and invasion through Matrigel. Interestingly, genome-wide expression profiling of cells expressing ARA70 beta revealed an increase in the expression of genes involved in the control of cell division and adhesion, compatible with a role for ARA70 beta in proliferation and invasion. Consistent with its function in promoting cell growth and invasion, ARA70 beta expression was increased in prostate cancer. Our findings implicate ARA70 beta as a regulator of tumor cell growth and metastasis by affecting gene expression.
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PMID:Stimulation of prostate cancer cellular proliferation and invasion by the androgen receptor co-activator ARA70. 1847 60

Despite being well recognized as the best biomarker for prostate cancer, pathophysiologic roles of prostate-specific antigen (PSA) remain unclear. We report here that tissue PSA may be involved in the hormone-refractory prostate cancer progression. Histologic analyses show that the increased tissue PSA levels are correlated with lower cell apoptosis index and higher cell proliferation rate in hormone-refractory tumor specimens. By stably transfecting PSA cDNA into various prostate cancer cell lines, we found that PSA could promote the growth of androgen receptor (AR)-positive CWR22rv1 and high-passage LNCaP (hormone-refractory prostate cancer cells) but not that of AR-negative PC-3 and DU145 cells. Surprisingly, the protease activity of PSA is not crucial for PSA to stimulate growth and promote AR transactivation. We further showed that increased PSA could enhance ARA70-induced AR transactivation via modulating the p53 pathway that results in the decreased apoptosis and increased cell proliferation in prostate cancer cells. Knockdown of PSA in LNCaP and CWR22rv1 cells causes cell apoptosis and cell growth arrest at the G(1) phase. In vitro colony formation assay and in vivo xenografted tumor results showed the suppression of prostate cancer growth via targeting PSA expression. Collectively, our findings suggest that, in addition to being a biomarker, PSA may also become a new potential therapeutic target for prostate cancer. PSA small interfering RNA or smaller molecules that can degrade PSA protein may be developed as alternative approaches to treat the prostate cancer.
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PMID:Tissue prostate-specific antigen facilitates refractory prostate tumor progression via enhancing ARA70-regulated androgen receptor transactivation. 1875 26

A single nucleotide polymorphism (SNP) at 10q11 (rs10993994) in the 5' region of the MSMB gene was recently implicated in prostate cancer risk in two genome-wide association studies. To identify possible causal variants in the region, we genotyped 16 tagging SNPs and imputed 29 additional SNPs in approximately 65 kb genomic region at 10q11 in a Swedish population-based case-control study (CAncer of the Prostate in Sweden), including 2899 cases and 1722 controls. We found evidence for two independent loci, separated by a recombination hotspot, associated with prostate cancer risk. Among multiple significant SNPs at locus 1, the initial SNP rs10993994 was most significant. Importantly, using an MSMB promoter reporter assay, we showed that the risk allele of this SNP had only 13% of the promoter activity of the wild-type allele in a prostate cancer model, LNCaP cells. Curiously, the second, novel locus (locus 2) was within NCOA4 (also known as ARA70), which is known to enhance androgen receptor transcriptional activity in prostate cancer cells. However, its association was only weakly confirmed in one of the three additional study populations. The observations that rs10993994 is the strongest associated variant in the region and its risk allele has a major effect on the transcriptional activity of MSMB, a gene with previously described prostate cancer suppressor function, together suggest the T allele of rs10993994 as a potential causal variant at 10q11 that confers increased risk of prostate cancer.
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PMID:Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk. 1915 72

Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70beta, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70alpha, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA70alpha is AR-dependent and mediated through induction of apoptosis rather than cell cycle arrest. Interestingly, AR with T877A mutation in LNCaP cells decreased its physical and functional interaction with ARA70alpha, facilitating the growth of LNCaP cells. The tumor suppressor function of ARA70alpha is consistent with our previous findings that ARA70alpha expression is decreased in prostate cancer cells compared with benign prostate. ARA70alpha also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70alpha is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70alpha functions as a tumor suppressor gene.
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PMID:Tumor suppressor function of androgen receptor coactivator ARA70alpha in prostate cancer. 2016 64


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