Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although prostate-specific antigen (PSA) is considered a uniquely important tumor marker and is broadly used for early detection of prostate cancer, the molecular mechanisms underlying its elevated expression in tumors have been unknown. By using cDNA microarray gene expression profiling, we found a fourfold increase in the PSA mRNA level in prostatic carcinoma cell line LNCaP, in which the p53 pathway was suppressed by a dominant negative p53 mutant. Consistently, p53 suppression caused a 4-8-fold increase in secretion of PSA protein in culture medium, suggesting that PSA gene expression is under negative control of p53. While wild type p53 strongly repressed, dominant negative p53 mutants stimulated PSA promoter-driven transcription and secretion of PSA in transient transfection experiments. The inhibitory effect of wild type p53 was undetectable in the presence of trichostatin A, suggesting the involvement of histone deacetylation in negative regulation of PSA promoter activity. Thus, PSA is likely to be a tissue specific indicator of transformation-associated p53 suppression in prostate cells. This finding provides a plausible explanation for a frequent increase of PSA levels in advanced prostate cancer.
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PMID:Expression of prostate specific antigen (PSA) is negatively regulated by p53. 1179 Nov 86

We have identified two novel polymorphisms in the prostate-specific antigen (PSA) gene promoter regions, the A-AA allele and G-A allele. Furthermore, we have found that A-AA occurred frequently in tumors with higher PSA expressions. We hypothesize that allelic differences may be associated with different phenotypes of breast cancer. To test this hypothesis, we assayed the PSA genotype for 101 breast cancer cases. We also performed immunostaining analysis for estrogen receptor, p53, MIB-1 and c-erbB-2 on all the tumors. At the time of diagnosis, the A-AA allele occurred more frequently in the tumors characterized by small tumor size, good to moderate differentiation, p53-negativity and low tumor proliferation activity. Our results suggest that the presence of the A-AA allele at the PSA promoter region is associated with less aggressive forms of breast cancer and could be looked on as a favorable prognostic factor.
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PMID:Correlation of prostate-specific antigen promoter polymorphisms with clinicopathological characteristics in breast cancer. 1216 76

PC-SPES is a potent eight-herb formulation sold directly to consumers; it has promising efficacy in the treatment of prostate cancer (CaP). The product induces a castrate status in most, if not all, men, resulting in a 50% or greater prostate-specific antigen reduction in the great majority of men with androgen-dependent CaP and in more than one half of the men with androgen-independent CaP. The duration of response is not yet clear. The efficacy of PC-SPES appears to exceed that of androgen ablation alone, but is not necessarily separate from an estrogenic effect. Common side effects include gynecomastia, nipple tenderness, loss of libido, and impotency; uncommon side effects include a 4% incidence of thromboembolic phenomena, but also two reports of bleeding diatheses. The mechanisms of action may involve downregulation of the androgen receptor, induction of apoptosis by way of inhibition of the bcl-2 gene, and increased expression of p53. Two marker compounds in PC-SPES are baicalin and oridonin, both of which exhibit antiproliferative effects in CaP cell lines. Thousands of men are currently obtaining this nonprescription medicine, and physicians should ask patients specifically about its use. PC-SPES is of great interest in men with androgen-independent CaP, an area in which future research should be primarily directed.
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PMID:PC-SPES: herbal formulation for prostate cancer. 1280 31

Prostate cancer prevention by key elements present in human nutrients derived from plants and fruits has been confirmed in various cell cultures and tumor models. Resveratrol (RE), a phytoalexin, induces remarkable inhibitory effects in prostate carcinogenesis via diverse cellular mechanisms associated with tumor initiation, promotion and progression. Earlier studies have shown that RE alters the expression of genes involved in cell cycle regulation and apoptosis, including cyclins, cdks, p53 and cdk inhibitors. However, most of the p53-controlled effects related to the role of RE in transcription either by activation or repression of a sizable number of primary and secondary target genes have not been investigated. Our study examined whether RE activates a cascade of p53-directed genes that are involved in apoptosis mechanism(s) or whether it modifies the androgen receptor and its co-activators directly or indirectly and induces cell growth inhibition. We demonstrate by DNA microarray, RT-PCR, Western blot and immunofluorescence analyses that treatment of androgen-sensitive prostate cancer cells (LNCaP) with 10(-5) M RE for 48 hr downregulates prostate-specific antigen (PSA), AR co-activator ARA 24 and NF-kB p65. Altered expression of these genes is associated with an activation of p53-responsive genes such as p53, PIG 7, p21(Waf1-Cip1), p300/CBP and Apaf-1. The effect of RE on p300/CBP plays a central role in its cancer preventive mechanisms in LNCaP cells. Our results implicate activation of more than one set of functionally related molecular targets. At this point we have identified some of the key molecular targets associated with AR and p53 target genes. These findings point to the need for further extensive studies on AR co-activators, such as p300, its central role in post-translational modifications such as acetylation of p53 and/or AR by RE in a time- and dose-dependent manner at different stages of prostate cancer that will fully elucidate the role of RE as a chemopreventive agent for prostate cancer in humans.
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PMID:Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. 2727 1

Mutations of p53 are common in hormone-refractory prostate cancer (CaP), suggesting the possibility that these mutations may be involved in the progression of CaP to androgen-independent (AI) growth. However, at present no direct evidence has been presented linking p53 mutations with AI growth of CaP. We established five stably transfected LNCaP cell lines: four containing gain-of-function (GOF) mutant p53 alleles (G245S, R248W, R273H, and R273C) and one containing a non-GOF p53 mutant allele (P151S). The four GOF p53 sublines were able to grow under androgen-depleted conditions, whereas the LNCaP parental line, vector-only line, and the non-GOF line were unable to grow. To investigate the mechanism of the AI growth displayed by the GOF p53 mutants, Western blotting or ELISA were used to examine the expression of the androgen receptor (AR), the AR-regulated prostate-specific antigen (PSA), as well as Akt and Bcl-2 under androgen-depleted conditions. On androgen ablation, the levels of AR decreased in the four GOF p53 sublines compared with the control lines. This decreased AR expression was accompanied by attenuated receptor activity, because a decrease in prostate-specific antigen levels compared with parental LNCaP cells was also observed. Levels of phosphorylated Akt increased in both the GOF p53 sublines and the control lines. Bcl-2 remains unchanged or showed reduced expression in all of the cell lines in the absence of androgen compared to the presence of androgen. These observations suggest that GOF p53 mutants mediate the AI growth of LNCaP cells in an AR-independent fashion, and that both Akt and Bcl-2 are not involved in this process.
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PMID:Androgen-independent growth of LNCaP prostate cancer cells is mediated by gain-of-function mutant p53. 1272 44

Pathologic characteristics of the prostatic adenocarcinoma in Koreans are not clear. We studied 132 cases of prostatectomy specimens using mapping analysis to discover the pathologic characteristics of the Korean prostatic adenocarcinoma. Mean values were as follows: serum prostate-specific antigen level (sPSA), 16.4 ng/ml; tumor volume, 27.5%; size, 2.4 cm; Gleason score, 7.7; and p53 expression, 9.8%. Rates of multifocal tumors and high-grade prostatic intraepithelial neoplasm (HPIN) were 33.3 and 65.2%. The Gleason score, tumor volume%, tumor size and sPSA were correlated with each other. Korean prostatic adenocarcinomas showed higher Gleason scores, lower rates of HPIN and multifocality, and lower p53 expression in comparison to Western prostatic adenocarcinomas. These data may be a basis for pathologic characteristics of Korean prostatic adenocarcinoma that has now been increasing.
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PMID:Pathologic characteristics of prostatic adenocarcinomas: a mapping analysis of Korean patients. 1280 73

Use of dietary supplements and botanical products is widely accepted by patients diagnosed with prostate cancer (CaP) as a primary or complementary form of treatment for their medical conditions in the U.S. Yet, the majority of these products have not been rigorously studied with regard to scientific mechanism(s). Because many of the available products are mixtures of multiple extracts derived from plants, some of which are not necessarily native to the U.S., we consider mechanistic studies under defined laboratory conditions to be valuable and essential, not only from the standpoint of standardization and possible contamination with the products, but also in providing insights and scientific evidence for the clinical efficacy some of these products purportedly demonstrate. In previous studies from this laboratory, Equiguard, a composite supplement consisting of standardized extracts from nine Chinese herbs, which was originally formulated to correct physiological decline in kidney functions associated with age, was fortuitously found to display anti-CaP properties. Using a panel of CaP cells, we showed that ethanol extracts of Equiguard significantly inhibited cancer cell growth, induced apoptosis, lowered expression of the androgen receptor (AR), decreased intracellular and secreted prostate-specific antigen (PSA) levels and completely abolished the colony forming activities of CaP cells. Since responsiveness to Equiguard was observed in cells mimicking the androgen-dependent (AD) and androgen-independent (AI) states of CaP, our results raise the interesting possibility that this herbal supplement may potentially prevent, delay or circumvent the onset of AI, and thereby induce chronic instead of terminal CaP. Since androgen ablation therapy (chemical or surgical castration) is the mainstay for localized CaP, we questioned whether Equiguard might still exert the aforementioned activities in experimental settings modeled after androgen ablation. Accordingly, we studied the effects of Equiguard in LNCaP cells, cultured in androgen-proficient (FBS) or -deficient (CS-FBS) media that simulate the hormonal status pre- and post-castration in vivo. Extracts of Equiguard were effective in reducing colony formation, proliferation and PCNA expression of cells cultured in CS-FBS. Moreover, within a concentration range of Equiguard, the prostate-specific genes, PSA and AR, were affected to a similar extent in cells cultured either in FBS or CS-FBS, and were correlated with increased phosphorylation at serine-15 of the tumor suppressor gene p53. These results are consistent with the interpretation that the anti-proliferative and gene modulatory properties of Equiguard are largely independent of the status of androgens in the culture media.
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PMID:Inhibition of proliferation and expression of AR/PSA by herbal supplement Equiguard in LNCaP cells cultured in androgen-proficient FBS and androgen-deficient charcoal-stripped FBS is correlated with increased serine-15 phosphorylation of the tumor suppressor gene p53. 1289 32

Telomerase is expressed in most types of tumor cells but not in most somatic cells, suggesting that telomerase inhibitors may be a powerful new approach to cancer chemotherapy. Here we explore this hypothesis by treating cultured human tumor cells with a 2'-O-methoxyethyl oligonucleotide that binds the telomerase RNA template and acts as a potent inhibitor. Treatment of DU145 (Rb(-), p53(-)) and LNCaP (Rb(+), p53(+)) cells causes telomeres to shorten and cell proliferation to stop. Decreased cell proliferation in culture is not observed immediately but occurs after several weeks and is accompanied by telomere shortening. Antiproliferative effects are more profound for cells growing in soft agar or in colony formation assays, with 90% reduction in the colony-forming ability of LNCaP cells after less than 2 weeks of exposure to the inhibitor. Decreased growth of DU145 and LNCaP tumors and large reductions in prostate-specific antigen levels are also observed in vivo in xenograft models. Short-term treatment of cells with telomerase inhibitors does not increase the effects of standard antiproliferative agents paclitaxel, doxorubicin, etoposide, cisplatin, or carboplatin. Long-term inhibition and telomere shortening sensitize DU145 cells, but not LNCaP cells, to cisplatin or carboplatin. These results demonstrate that methoxyethyl oligomers directed against the template region of telomerase are potent agents and that significant antiproliferative effects can be observed after 2-3 weeks of treatment. Reduced cell proliferation and tumor growth support the hypothesis that telomerase inhibition can make a useful contribution to chemotherapy and should encourage broad testing of telomerase inhibitors.
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PMID:Consequences of telomerase inhibition and combination treatments for the proliferation of cancer cells. 1452 18

In recent studies, we found that sulindac sulfide (SS), exisulind, CP248, and CP461 induce growth inhibition and apoptosis in a series of human prostate cancer cell lines, irrespective of cyclooxygenase expression, p53 mutations, or bcl-2 overexpression. Exisulind also inhibited the growth of the androgen-dependent LNCaP human prostate cancer cell line when grown as a xenograft in nude mice. This study demonstrates that doses of these compounds that induce growth inhibition and apoptosis in LNCaP cells also cause decreased prostate-specific antigen (PSA) secretion and decreased cellular levels of PSA. These effects appear to be a result, at least in part, of inhibition of the androgen receptor (AR) signaling pathway because the treated cells also display decreases in the level of the AR protein and mRNA and inhibition of transcription of an AR promoter luciferase reporter in transient transfection assays. SS and exisulind were more effective in inhibiting the expression of PSA and the AR than CP248 or CP461, apparently because of differential effects of these compounds on specific transcription factors. These findings suggest that the growth inhibition by these compounds in human prostate cancer cells may be mediated, in part, by inhibition of AR signaling. Thus, these compounds may provide a novel approach to the prevention and treatment of human prostate cancer.
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PMID:Exisulind and related compounds inhibit expression and function of the androgen receptor in human prostate cancer cells. 1458 72

The underlying basis for rising levels of prostate-specific antigen (PSA) in prostate cancer is not fully understood, but attention has turned to the possibility that loss of normal p53 function might be directly involved. We have investigated the relationship between p53 function and PSA expression using in vitro and in vivo approaches. Three prostate cancer-derived p53 mutants (F134L, M237L, R273H) were introduced into LNCaP prostate cancer cells and stable transfectants established. Expression of mutant p53 was demonstrated by Western blot analysis, inactivation of wtp53 function, and a loss of p53-dependent responses to DNA damage induced by UV-irradiation and cisplatin. Levels of PSA mRNA and secreted protein were determined by RT-PCR and Western blotting, respectively. Serine protease activity was assessed using an esterase assay. In vivo effects of mutant p53 expression were examined after orthotopic implantation into prostates of nude mice. Expression of all p53 mutants was associated with elevated PSA mRNA and secreted PSA protein. In a representative line, mutant p53 was also associated with increased PSA protease-like activity compared with a control line expressing wildtype p53. Overall PSA levels, and PSA levels in serum from mice bearing tumors derived from cells expressing mutant p53, were increased compared with levels in mice bearing tumors derived from control cells. In addition, the tumors derived from cells with mutant p53 had increased vascularization and induced lymph node metastases. These data provide in vitro and in vivo support for the notion that p53 mutations directly contribute to increased levels of serum PSA, and are associated with more aggressive tumors.
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PMID:Elevated levels of prostate-specific antigen (PSA) in prostate cancer cells expressing mutant p53 is associated with tumor metastasis. 1458 98


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