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)

Arachidonic acid (AA) metabolites derived from both cyclooxygenase (COX) and lipoxygenase (LOX) pathways transduce a variety of signals related to cell growth. Here, we report that the AA LOX pathway also functions as a critical regulator of cell survival and apoptosis. Rat Walker 256 (W256) carcinosarcoma cells express 12-LOX and synthesize 12(S)- and 15(S)-hydroxyeicosatetraenoic acids as their major LOX metabolites. W256 cells transfected with 12-LOX-specific antisense oligonucleotide or antisense oligonucleotides directed to conserved regions of LOXs underwent time- and dose-dependent apoptosis. Likewise, treatment of W256 cells with various LOX but not COX inhibitors induced apoptotic cell death, which could be partially inhibited by exogenous 12(S)- or 15(S)-hydroxyeicosatetraenoic acids. The W256 cell apoptosis induced by antisense oligos and LOX inhibitors was followed by a rapid downregulation of bcl-2 protein, a dramatic decrease in the bcl-2/bax ratio, and could be suppressed by bcl-2 overexpression. In contrast, p53, which is wild type in W256 cells, did not undergo alterations during apoptosis induction. The results suggest that the LOX pathway plays an important physiological role in regulating apoptosis.
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PMID:Arachidonate lipoxygenases as essential regulators of cell survival and apoptosis. 864 60

The widespread use of prostate-specific antigen (PSA) has revealed that radiation therapy cures adenocarcinoma of the prostate less frequently than previously believed. Biologic factors (such as the complex nature of this disease) and technical factors (geographic miss, inadequate dose to the tumor volume) affect the ability of radiation to effectively treat all patients with prostate cancer. To improve treatment outcome, patients with virulent forms of the disease must be identified. The use of prognostic markers (PSA, prostate-specific membrane antigen, prostate-specific antigen doubling time) and genetic markers (12 lipoxygenase, p53, bcl-2, ploidy) may aid in the development of treatments for these patients. Technical modifications have been made to increase the total dose delivered to the prostate and the accuracy of dose delivery. Brachytherapy, proton therapy and conformal radiation therapy have been used to increase the relative integral dose. Improved prostate targeting may be achieved with the use of fiducial markers, on-line portal imaging, and endorectal magnetic resonance imaging. High linear energy transfer radiation, radiosensitizers and altered fractionation have been used in an attempt to increase the biologic equivalent dose to the tumor. Lastly, hormonal therapy and chemotherapy have been shown to decrease tumor burden and improve local control. All of these methods may improve outcome in patients with adenocarcinoma of the prostate. However, further work must be completed to translate these methods into standards of care.
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PMID:A rational approach to the treatment of prostate cancer with radiation therapy: lessons for the future. 942 69

APO2L (TRAIL) is a novel CD95L (Fas/APO-1-L) homologous cytotoxic cytokine that interacts with various receptors which transmit (DR4, DR5) or inhibit (DcR1, DcR2) an apoptotic signal. Here, we report that human glioma cell lines preferentially express mRNAs for agonistic death receptors DR4 (8/12) and DR5 (11/12) rather than the death-inhibitory decoy receptors DcR1 (4/12) and DcR2 (2/12). Ten of 12 cell lines are susceptible to APO2L-induced apoptosis. The resistant cell lines, U138MG and U373MG, are cross-resistant to CD95L-induced apoptosis. Similar to CD95L-induced apoptosis, APO2L-induced apoptosis is inhibited by ectopic expression of the caspase inhibitor, crm-A, or of bcl-2, or by coexposure to the corticosteroid, dexamethasone, or the lipoxygenase inhibitor, nordihydroguaretic acid. There is no correlation between p53 genetic status of the cell lines and their susceptibility to APO2L-induced apoptosis, but the latter is moderately enhanced by ectopic expression of wild-type p53. APO2L targeting may be a promising approach for selectively targeting apoptosis to human malignant glioma cells.
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PMID:APO2 ligand: a novel lethal weapon against malignant glioma? 961 12

The role of long-chain polyunsaturated fatty acids (PUFA) in the etiopathology and treatment of cancer is poorly understood. We have studied the effects of n;-3 and n;-6 PUFA on the proliferation and survival of normal human uroepithelial (NHU) cells, cells with disabled p53 function after stable transfection with the human papillomavirus 16 (HPV16) E6 gene (HU-E6), and p53-disabled cells that had passed through crisis and acquired karyotypic abnormalities (HU-E6P). The n;-3 and n;-6 PUFA had distinct reversible antiproliferative and irreversible cytostatic effects according to concentration and exposure time. The reversible antiproliferative effect was partly due to the production of lipoxygenase metabolites. NHU and HU-E6 cells were equally sensitive to n;-3 and n;-6 PUFA, but HU-E6P cells were more resistant to both the antiproliferative and cytostatic effects. Cytostatic concentrations of n;-3 and n;-6 PUFA did not induce apoptosis, but caused permanent growth arrest ("interphase" or "reproductive" cell death) and mRNA levels for genes involved in cell cycle control (p21, p16, p27, cdk1, cdk2, and cdk4) were not altered. Neither n;-3 nor n;-6 PUFA promoted acquisition of karyotypic abnormalities in HU-E6 cells, suggesting that n;-3 and n;-6 PUFA do not cause genotoxic damage. In conclusion, our studies show that the antiproliferative and cytostatic effects of n;-3 and n;-6 PUFA are not dependent on p53 function and, further, that transformation results in a loss of sensitivity to n;-3 and n;-6 PUFA-mediated growth inhibition.
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PMID:N;-3 and n;-6 polyunsaturated fatty acids induce cytostasis in human urothelial cells independent of p53 gene function. 1097 58

Although aflatoxin B1 (AFB1) is best known as a hepatocarcinogen, the respiratory system can also be a target of this mycotoxin. In isolated lung cells from rabbits and mice, AFB1 is bioactivated by cytochromes P450, primarily in nonciliated bronchiolar epithelial (Clara) cells. However, mutagenesis experiments suggest that the DNA-binding AFB1 epoxide metabolite can leave the cells of origin, and potentially interact with other cell types. Consistent with DNA adduct studies, AFB1-induced AC3F1 mouse lung tumors contain point mutations at guanine residues in K-ras, with the anticipated bias for the A/J allele. Furthermore, following AFB1 treatment but prior to tumor development, K-ras mutations occur preferentially in mouse Clara cells. However, in contrast to findings with other carcinogens, AFB1-induced mouse lung tumors demonstrate frequent, but heterogeneously distributed, overexpression of p53 protein as well as p53 point mutations, suggesting a carcinogen-specific response. Unlike lung tissue from mice and rabbits, human peripheral lung bioactivates AFB1 primarily by prostaglandin H synthase--and/or lipoxygenase-catalyzed cooxidation, with activity concentrated in macrophages. In addition, although glutathione S-transferase M1-1 has high specific activity for AFB1 epoxide conjugation, lung tissues from GSTM1-null individuals do not demonstrate diminished rates of conjugation, compared to tissues from GSTM1-positive individuals. In summary, AFB1 tumorigenesis in mice demonstrates unique properties, and processes of bioactivation show significant species differences.
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PMID:Mechanisms of aflatoxin B1 lung tumorigenesis. 1119 64

Biologic factors affect the ability of radiation to effectively treat all patients with prostate cancer. The use of prognostic and genetic markers (12 lipoxygenase, p53, bc1-2 genes, ploidy) may aid in the development of treatments for these patients. Particularly, several studies have shown that p53 tumor suppressor gene mutations are infrequent in prostate cancer and are associated with advanced disease. Recent efforts have been directed toward novel therapeutic modalities, especially in combination with standard irradiation of prostate carcinoma. These modalities are based on an improved knowledge of these biological factors involved in the progression and diffusion of the tumor, especially p53. Several authors evaluated the predictive and prognostic role of p53 in patients with prostatic cancer treated with radiotherapy. An extensive review of international reports on the subject is provided.
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PMID:Biological factors and therapeutic modulation in prostate cancer radiotherapy. 1269 51

Flavonoids (FVs) are an important class of plant compounds postulated to be one of the constituents responsible for the beneficial effects of fruits and vegetables on health, including heart disease and cancer. At pharmacological levels, various naturally-occurring flavonoids have been shown to be cancer-protective in a variety of animal models and flavonoid derivatives, such as flavopyridol, are being assessed as chemotherapy drugs in clinical trials. This report has investigated the effects of the most common dietary FVs on several major signalling pathways in biopsies of human epithelial cells using primary cultures freshly isolated from biopsies and has obtained evidence for the previously unrecognised importance of stress kinase responses induced by kaempferol (KF), apigenin (AP) and luteolin (LU). KF, AP and LU all activated ATM/ATR (mutated in ataxia-telangiectasia and related) kinases and the p38 stress kinase and this was associated with induction of GADD45 and cell cycle arrest in G2, but not induction of apoptosis. These effects were not due to general toxicity since they were reversible on removal of FV. The inductions of ATM/ATR and p38 were functionally important since caffeine, an inhibitor of ATM/ATR, and the p38-specific inhibitor, SB203580, prevented induction of GADD45 and growth arrest by these three flavonoids. In contrast, although quercetin (QU) activated ATM (but not ATR), it did not activate p38 kinase, GADD45 or p53. QU may interfere with one of the lipoxygenase (LOX) pathways since the growth inhibitory effects of QU (but not the other three flavonoids) could be reversed by addition of LOX metabolites, particularly 12- and 15-hydroxyeicostetraenic acids.
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PMID:Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells. 1460 32

Curcumin (diferuloylmethane) is being considered as a potential chemopreventive agent in humans. In vitro it inhibits transcription by NF-kappaB, and the activity of lipoxygenase or cyclooxygenase enzymes, which facilitate tumor progression. In vivo it is protective in rodent models of chemical carcinogenesis. Curcumin contains an alpha,beta-unsaturated ketone, a reactive chemical substituent that is responsible for its repression of NF-kappaB. In compounds other than curcumin this same electrophilic moiety is associated with inactivation of the tumor suppressor, p53. Here we report that curcumin behaves analogously to these compounds. It disrupts the conformation of the p53 protein required for its serine phosphorylation, its binding to DNA, its transactivation of p53-responsive genes and p53-mediated cell cycle arrest.
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PMID:Curcumin impairs tumor suppressor p53 function in colon cancer cells. 1509 Apr 65

Many natural components of plant extracts are studied for their beneficial effects for health and particularly on carcinogenesis chemoprevention. In the present study, we investigated the effects of diosgenin on erythroleukemia HEL cells. Our results demonstrated that diosgenin induced G2/M arrest of cell cycle progression through p21 up-regulation in a p53-independent pathway and strong induction of apoptosis in HEL cells. Apoptosis induction was accompanied by an increase in Bax/Bcl-2 ratio, PARP cleavage and DNA fragmentation. Moreover, we showed for the first time that diosgenin provoked a collapse of mitochondrial membrane potential with an increase in intracellular calcium levels. It is well known that [Ca2+]i increase is one of the major activators of cytosolic PLA2. In our study, we demonstrated that diosgenin treatment induced cPLA2 activation through translocation to the cellular membrane. Moreover, arachidonic acid metabolism activation led to cyclooxygenase-2 (COX-2) but not lipoxygenase overexpression. Surprisingly, we observed a COX-2 up-regulation associated with apoptosis induction by diosgenin. These findings suggest that diosgenin has a potential chemopreventive effect; future studies should evaluate the mechanism of COX-2 activation during diosgenin-induced apoptosis in cancer cell lines.
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PMID:Diosgenin induces cell cycle arrest and apoptosis in HEL cells with increase in intracellular calcium level, activation of cPLA2 and COX-2 overexpression. 1528 56

Tumor suppressor function for Annexin A7 (ANXA7; 10q21) is based on cancer-prone phenotype in Anxa7(+/-) mouse and ANXA7 prognostic role in human cancers. Because ANXA7-caused liposome aggregation can be promoted by arachidonic acid (AA), we hypothesized that the phospholipid-binding tumor suppressor ANXA7 is associated with AA cascade. In a comparative study of ANXA7 versus canonical tumor suppressor p53 effects on AA lipoxygenation pathway in the p53-mutant and androgen-insensitive DU145 prostate cancer cells, both tumor suppressors altered gene expression of major 5-lipoxygenase (LOX) and 15-LOXs, including response to T helper 2 (Th2)-cytokine [interleukin-4 (IL-4)] and endogenous steroids (mimicked by dexamethasone). Wild-type and mutant ANXA7 distinctly affected expression of the dexamethasone-induced 15-LOX-2 (a prostate-specific endogenous tumor suppressor) as well as the IL-4-induced 15-LOX-1. On the other hand, wild-type p53 restored 5-LOX expression in DU145 to levels comparable to benign prostate epithelial cells. Using mass spectrometry of DNA affinity-enriched nuclear proteins, we detected different proteins that were bound to adjacent p53 and estrogen response elements in the 5-LOX promoter in DU145 cells introduced with ANXA7 versus p53. Sex hormone regulator 17-beta hydroxysteroid dehydrogenase 4 was identified under p53 introduction, which induced the 5-LOX expression. Meantime, nuclear proteins bound to the same 5-LOX promoter site under introduction of ANXA7 (that was associated with the repressed 5-LOX) were identified as zinc finger proteins ZNF433 and Aiolos, pyrin domain-containing NALP10, and the p53-regulating DNA repair enzyme APEX1. Thus, ANXA7 and p53 can distinctly regulate LOX transcription that is potentially relevant to the AA-mediated cell growth control in tumor suppression.
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PMID:Distinct effects of annexin A7 and p53 on arachidonate lipoxygenation in prostate cancer cells involve 5-lipoxygenase transcription. 1701 18


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