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)

A common mutation in P53 protein occurs at amino acid residue 281 in the DNA binding domain (P53(gly(281))), which results in loss of transcriptional regulation of P53 target genes and has been reported to gain pro-oncogenic functions. In the present study, we investigated the activity of P53(gly(281)) in P53-null PC3 human prostate cancer cells and found that the P53(gly(281)) induced apoptosis as efficiently as the wild-type P53 (wtP53). However, in contrast to wtP53-induced apoptosis, the P53(gly(281))-induced apoptosis was insensitive to overexpression of bcl-2. Thus, our findings indicate that while a mutation in the DNA binding domain of p53 may result in a more oncogenic form of the protein, it may also paradoxically result in the 'gain' of a new, alternative pathway for apoptosis.
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PMID:A mutant P53 can activate apoptosis through a mechanism distinct from those induced by wild type P53. 1206 26

Using a binary co-transfection strategy of Ad/GT Bax and Ad/PGK-GV16, we have succeeded in inducing overexpression of Bax protein in three prostate cell lines (androgen-insensitive DU145 and PC3, and androgen-sensitive LNCaP). The expression of Bax protein by this system was sufficient to induce all three prostate lines to undergo apoptosis. The fact that DU145 cells which have a p53 mutation and are deficient in Bax, responded to this treatment, suggests that this effect is independent of these pathways. Initiation of the cleavage of Caspase-3 (CPP32/Yama/apopain) and PARP (poly (ADP-ribose) polymerase) by the introduction of Bax were confirmed by western blot analysis. Bcl-2 expression is relevant in the progression of prostate cancer and contributes to an androgen, apoptotic-resistant phenotype in the advanced stages. We examined stable Bcl-2 overexpressing DU145, PC3 and LNCaP cell lines as models of advanced prostate cancer. The adenoviral co-transfection system induced Bax protein expression and apoptosis even in these Bcl-2 transfected cell lines. Taken together, our results suggest that this Bax expression system might represent a useful gene therapy strategy when applied to the treatment of prostate cancer and its efficacy would be independent of the Bcl-2 status and androgen sensitivity of these cancers.
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PMID:A recombinant adenovirus expressing wild-type Bax induces apoptosis in prostate cancer cells independently of their Bcl-2 status and androgen sensitivity. 1217 Jul 76

We recently reported on a prostate cancer progression model which was based on repeated orthotopic implantation of human prostate cancer cell lines into athymic nude mice leading to an increase of tumor cell aggressiveness. To assess progression-associated clonal evolution of genotypic changes, we now performed comparative cytogenetic characterization of the original cell lines DU145 and PC3 with derived sublines DU145MN1 and PC3-N. Cell line PC3-125-1L, isolated from a lung metastasis after subcutaneous inoculation of PC3 into nude mice, was included in the study. Whole-genome analysis was performed using spectral karyotyping and comparative genomic hybridization. Fluorescence in situ hybridization was used to assess amplification of selected genes, which are supposed to play a role in prostate cancer progression. Differences in the genetic constitution between parental cell lines and sublines involved gains of genetic material at 2q, 5q, 12p/q, and 18p as well as losses at 6p, 7q, 17p, 18q, and 22q. Loss of 17p in DU145MN1 and high-level amplification of MYC in PC3-125-1L resulted in loss of p53 expression and upregulation of Myc expression, respectively, as was assessed by Western blotting. Thus, the nude mice model is very useful to follow clonal evolution of genetic changes during increase of prostate cancer aggressiveness and possibly to clone genes associated with the progression of prostate cancer.
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PMID:Comprehensive genotypic analysis of human prostate cancer cell lines and sublines derived from metastases after orthotopic implantation in nude mice. 1223 7

The p53-transcriptional target, BTG2(TIS21/PC3), was previously identified as an antiproliferative gene. However, the precise biological functions of the protein product remain to be elucidated. BTG2(TIS21/PC3) expression is induced in vivo during neurogenesis, and the gene is transiently expressed in vitro in rat pheochromocytoma PC12 cells after induction of neuronal differentiation by addition of nerve growth factor (NGF). These observations suggest that BTG2(TIS21/PC3) is functionally significant during the neuronal differentiation process. To test this hypothesis, a vector that expressed BTG2(TIS21/PC3) under the control of an inducible promoter was introduced into PC12 cells. Growth arrest and differentiation in response to NGF were greatly enhanced by BTG2(TIS21/PC3) overexpression. Furthermore, an antisense oligonucleotide complementary to BTG2(TIS21/PC3) mRNA, which was able to inhibit endogenous BTG2(TIS21/PC3) expression, triggered programmed cell death in differentiated PC12 cells. These observations confirm that BTG2(TIS21/PC3) expression promotes neuronal differentiation and that it is required for survival of terminally differentiated cells.
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PMID:BTG2(TIS21/PC3) induces neuronal differentiation and prevents apoptosis of terminally differentiated PC12 cells. 1236 Mar 98

ST1481, a lead compound of a novel potent 7-substituted lipophilic camptothecin series, is able to overcome several mechanisms of drug resistance and was selected for clinical development. This study was designed to examine the antitumor activity of ST1481 in the treatment of preclinical models of human p53-defective hormone-refractory prostate carcinoma (DU145, PC3, and JCA-1) and to explore the cellular bases of the efficacy of camptothecins. A cellular pharmacology study (cytotoxicity, apoptosis, cellular drug accumulation, DNA damage, and cell cycle perturbation) was performed in DU145 and PC3 cells, characterized by a different cell cycle checkpoint status. The introduction of wild-type p53 in PC3 cells appreciably decreased the drug sensitivity. The 7-substituted camptothecins exhibited a high cytotoxic potency that paralleled their relative ability to induce DNA damage and a substantially increased cellular accumulation as compared to topotecan. The cytotoxic effect of camptothecins in DU145 cells was associated with arrest in S phase and early activation of apoptosis, whereas PC3 cells responded to drugs by a persistent block in G2 phase with a cytostatic effect and a late apoptosis. The efficiency of S phase checkpoint in DU145 cells was supported by a time-dependent decrease of DNA synthesis following treatment. In spite of an apparent cytostatic response and apoptosis resistance, the PC3 tumor was more responsive to in vivo treatment with camptothecins than the DU145 model. Indeed, the therapeutic outcome did not reflect the cell susceptibility to early activation of apoptosis. We suggest that cell death in PC3 cells is a delayed event consequent to persistent arrest in G2 and insufficient repair of DNA damage. ST1481 was appreciably more effective than topotecan in all tested tumors. In conclusion, the results indicated a relevant efficacy of camptothecins against human prostate carcinoma models, in spite of p53 alterations. Although p53 status could influence DNA damage and cell cycle checkpoints, p53 mutation was not a determinant of resistance. The results support that, in addition to the extent and persistence of topoisomerase I-mediated DNA damage, cell cycle checkpoints and DNA damage signaling pathways are critical determinants of tumor responsiveness to camptothecins. A role of cell cycle checkpoints activated by DNA damage in cell response is supported by the modulation of transcriptional profile.
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PMID:Cellular bases of the antitumor activity of a 7-substituted camptothecin in hormone-refractory human prostate carcinoma models. 1269 69

Both inactivation of p53 function and loss of sensitivity to Fas contribute to a malignant phenotype and frequently occur during tumor progression. Although in the majority of cases only one of the p53 alleles is mutated, some tumors acquire mutations in both alleles of the p53 gene. To determine the biological significance of this phenomenon, we analyzed p53 mutants, p53(223Leu) and p53(274Phe), from Fas-resistant prostate carcinoma cell line DU145. Both mutants differed from wild-type p53 in their conformation, transactivation ability, and effect on the growth of p53-deficient cells, with p53(223Leu) being more similar to wild-type p53 than was p53(274Phe). Interestingly, the biological effect of coexpression of the DU145-derived mutants was dramatically different from that of each mutant expressed alone. Whereas neither of the two mutants was found to be dominant-negative against wild-type p53, each neutralized the other's growth-suppressive effects and, in combination, were capable of down-regulating Fas expression and converting Fas-sensitive prostate carcinoma cells PC3 into Fas-resistant ones. These results indicate that two different p53 mutants that are separately rather weak can cooperate to generate p53 protein with anti-Fas function that is likely to provide additional selective advantages to the tumor.
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PMID:Cooperation of two mutant p53 alleles contributes to Fas resistance of prostate carcinoma cells. 1278 97

PC-SPES is an eight herbal mixture that was shown to have activity against prostate cancer. Recently, we purified oridonin from Rabdosia rubescens, one component of PC-SPES, by high performance liquid chromatography (HPLC). The ability of oridonin to inhibit the proliferation of cancer cells was examined by MTT assay. Oridonin effectively inhibited the proliferation of a wide variety of cancer cells including those from prostate (LNCaP, DU145, PC3), breast (MCF-7, MDA-MB231), non-small cell lung (NSCL) (NCI-H520, NCI-H460, NCI-H1299) cancers, acute promyelocytic leukemia (NB4), and glioblastoma multiforme (U118, U138) with ED50s ranging from 1.8 to 7.5 micro g/ml. TUNEL assay and cell cycle analysis showed that oridonin induced apoptosis and G0/G1 cell cycle arrest in LNCaP prostate cancer cells. In addition, expression of p21waf1 was induced in LNCaP and NCI-H520 cells in a p53-dependent manner. Interestingly, when p53 was suppressed by over-expression of E6 from human papilloma virus type 16 (HPV-16), these cells lost their sensitivity to oridonin-induced growth inhibition and apoptosis. Taken together, oridonin inhibited the proliferation of cancer cells via apoptosis and cell cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies and probably represents one of the major, active components of PC-SPES.
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PMID:Oridonin induces growth inhibition and apoptosis of a variety of human cancer cells. 1296 3

This study was undertaken to investigate the role of mouse double minute 2 (MDM2) oncogene in prostate cancer growth and the potential of MDM2 as a target for prostate cancer therapy. An antisense anti-human-MDM2 mixed-backbone oligonucleotide was tested in human prostate cancer models with various p53 statuses, LNCaP (p53wt/wt), DU145 (p53mt/mt), and PC3 (p53null). In a dose- and time-dependent manner, it specifically inhibited MDM2 expression and modified expression of several genes, at both mRNA and protein levels. In LNCaP cells, p53, p21, Bax, and hypophosphorylated retinoblastoma tumor suppressor protein (pRb) levels increased, whereas Bcl2, pRb protein, and E2F transcription factor 1 (E2F1) levels decreased. In DU145 cells, p21 levels were elevated and E2F1 levels decreased, although mutant p53, Rb, and Bax levels remained unchanged. In PC3 cells, MDM2 inhibition resulted in elevated p21, Bax, and pRb levels and decreased ppRb and E2F1 levels. In all three cell lines, MDM2 inhibition reduced cell proliferation, induced apoptosis, and potentiated the effects of the chemotherapeutic agents 10-hydroxycamptothecin and paclitaxel. The anti-MDM2 oligonucleotide showed antitumor activity and increased therapeutic effectiveness of paclitaxel in both LNCaP and PC3 xenografts, causing changes in gene expression similar to those seen in vitro. In summary, this study demonstrates that MDM2 has a role in prostate cancer growth via p53-dependent and p53-independent mechanisms and that multiple genes are involved in the process. MDM2 inhibitors such as second-generation antisense oligonucleotides have a broad spectrum of antitumor activities in human cancers regardless of p53 status, providing novel approaches to therapy of human prostate cancer.
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PMID:Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy. 1313 78

Ribonucleotide reductase (RR) is responsible for the de novo conversion of the ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair. RR consists of two subunits, hRRM1 and hRRM2. p53R2 is a new RR family member. Because the majority of human tumors possess mutant p53, it is important to know the molecular mechanism by which mutant p53 regulates RR and to what extent. In this study, we investigated the expression and function of p53R2 and hRRM2 after UV treatment in human prostate cancer PC3 cells, which possess mutant p53 with a truncated COOH-terminal, and in human oropharyngeal cancer KB cells, which possess wild-type p53. p53R2 (analyzed by Western blot and standardized relative to Coomassie Blue-stained band) was down-regulated in PC3 cells and up-regulated in KB cells after UV exposure. In contrast, hRRM2 was up-regulated by UV in both PC3 cells and KB cells. hRRM2 and p53R2 mRNA levels were assessed by Northern blot, and the results paralleled that of the Western blot. Coimmunoprecipitation assays using agarose-conjugated goat antihuman RRM1 antibody confirmed that the p53R2 binding to hRRM1 decreased in PC3 cells but increased in KB cells after UV treatment. hRRM2 binding to hRRM1 increased in both cell lines under the same conditions. These results suggest that PC3 cells are deficient in both transcription of p53R2 and binding to hRRM1 in response to UV irradiation. Confocal microscopy further confirmed that these findings were not due to translocation of hRRM2 and p53R2 from the cytoplasm to the nucleus. RR activity was measured following UV treatment and shown to increase in PC3 cells. It was unchanged in proportional of KB cells. The RR activity is consistent with the expression of hRRM2 seen in the Western blots. Thus, we hypothesize that hRRM2 complements p53R2 to form RR holoenzyme and maintain RR activity in PC3 cells after UV treatment. To further confirm this hypothesis, we examined the effect of RRM2 inhibitors on cells exposed to UV. In PC3 cells, hydroxyurea inhibited hRRM2 and resulted in increased sensitivity to UV irradiation. We also examined the effect of UV treatment on the colony-forming ability of cells transfected with hRRM2 as well as p53R2 sense or antisense expression vectors. Expression of antisense hRRM2 in PC3 cells led to decreased hRRM2 expression and resulted in greater sensitivity to UV than observed in wild-type PC3 cells. Taken together, we conclude that UV-induced activation of p53R2 transcription and binding of p53R2 to hRRM1 to form RR holoenzyme are impaired in the p53-mutant cell line PC3.
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PMID:The human ribonucleotide reductase subunit hRRM2 complements p53R2 in response to UV-induced DNA repair in cells with mutant p53. 1458 50

External beam radiation therapy is an effective therapy for localized prostate cancer, although failures occur at high rates. One variable that may affect the radiosensitivity of prostate tumor cells is their p53 status because this gene controls radiation-induced cell cycle arrest, apoptosis, and the repair of DNA damage. Using a system in which p53 function was conditionally restored to p53-null PC3 prostate cancer cells by stable transfection with a human temperature-sensitive p53 mutant allele, we tested the hypothesis that functional p53 increases cell cycle arrest and contributes to increased clonogenic survival after ionizing radiation (IR) of prostate carcinoma cells. Cell cycle arrest and clonogenic survival in response to single and multiple daily exposures to clinically relevant 2-Gy doses of IR were examined. Whereas the temperature-sensitive p53 protein was activated by phosphorylation after IR exposure at both the restrictive and permissive temperatures, Cdkn1/p21 was only induced by functional p53 (at the permissive temperature). In the presence of functional p53, the maintenance of G(2) arrest was significantly longer (P < 0.01), and a small increase in cell survival measured by clonogenic assay was seen after exposure to a single 2-Gy dose of IR. However, functional p53 significantly increased clonogenic survival (P < 0.01) after exposure to daily doses of 2 Gy of IR and contributed to a more sustained G(2) arrest and increased G(1) arrest in response to the multifraction regimen. These studies implicate the presence of wild-type p53 with increased survival of prostate carcinoma cells after fractionated exposure to radiation. Additionally, the data provide evidence that wild-type p53 in prostate tumor cells may reduce the effectiveness of radiation therapy.
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PMID:Functional p53 increases prostate cancer cell survival after exposure to fractionated doses of ionizing radiation. 1461 13


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