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

Methylselenol has been implicated as an active metabolite for the anticancer effect of selenium in part through the induction of cancer cell apoptosis. Since inactivation of the AKT/protein kinase B negative regulator gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) is common in prostate cancer (PCa), we compared PTEN wild-type DU145 PCa cells (low basal AKT activity) with PTEN-mutant LNCaP PCa cells (high basal AKT activity) for their apoptosis responses to the methylselenol precursor methylseleninic acid (MSeA) and sodium selenite, an inorganic salt. Our results show that LNCaP cells withstood approximately 4 times higher doses of MSeA than DU145 cells, although they were slightly more sensitive than the latter to selenite-induced apoptosis. Treatment by MSeA modestly attenuated AKT phosphorylation and increased phospho-ERK1/2 in LNCaP cells. Selenite treatment increased the phosphorylation of p53 Ser15 and both kinases, but the selenite-induced apoptosis was not influenced by chemical inhibitors of either kinase. In contrast, PI3K/AKT inhibitors greatly sensitized LNCaP cells to apoptosis induced by MSeA, accompanied by increased mitochondrial release of cytochrome c and multiple caspase activation without changing p53 Ser15 phosphorylation. The apoptosis was further accentuated by extracellular signal regulated kinases 1 and 2 (ERK1/2) inhibition without further increase in cytochrome c release. The general caspase inhibitor z-VAD-fmk completely blocked MSeA-induced apoptosis when both kinases were inhibited, whereas a caspase-8 inhibitor exerted a greater protection than did a caspase-9 inhibitor. Transfection of DU145 cells with a constitutively active AKT increased their resistance to MSeA-induced apoptosis. In summary, AKT played an important role in regulating apoptosis sensitivity of LNCaP and DU145 cells to MSeA. An MSeA-induced activation of ERK1/2 in LNCaP cells also contributed to resistance to apoptosis. However, these kinases did not significantly regulate caspase-mediated apoptosis induced by selenite in LNCaP cells. These findings support the differential involvement of these protein kinase pathways in regulating apoptosis induction by different forms of selenium.
 ...
PMID:PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. 1584 51

Basic research and clinical chemoprevention trials support the protective role of selenium in cancer prevention but the mechanisms based on the molecular level remain to be fully defined. This mini-review focuses only on the elucidation of the molecular mechanisms of cancer prevention by selenium using the genomics approach; target organs discussed here are breast, prostate, colon and lung. The results described here support the utility of microarray technology in delineating the molecular mechanisms of cancer prevention by selenium. These results are based on studies employing human and rodent cell lines and tissues from animal models ranging from normal to frank cancer. The dose and the form of selenium are determining factors in cancer chemoprevention. The results of the microarray analysis reviewed here indicate that selenium, independent of its form and the target organ examined, alters several genes in a manner that can account for cancer prevention. Selenium can up regulate genes related to phase II detoxification enzymes, certain selenium-binding proteins and select apoptotic genes, while down regulating those related to phase I activating enzymes and cell proliferation. Independent of tissue type, selenium arrests cells in G1 phase of cell cycle, inhibits CYCLIN A, CYCLIN D1, CDC25A, CDK4, PCNA and E2F gene expressions while induces the expressions of P19, P21, P53, GST, SOD, NQO1, GADD153 and certain CASPASES. In addition to those described above, genes such as OPN, which is mainly involved in metastasis and recently reported to be down regulated by selenium, should be considered as potential molecular marker in clinical chemoprevention trials. Collectively, literature data indicate that some of these genes that were altered by selenium are also involved in the development of human cancers described in this review. It appears that androgen receptor status may influence the effect of selenium on gene expression profile in prostate cancer; whether estrogen receptor may influence the effect of selenium on gene expression in breast cancer requires further studies. Knowledge from gene array data in combination with proteomics approaches, using homogenous population of cell types with the aid of laser capture microdissection, may provide an individualized dimension of information on cancer risk and potential targets for its prevention. The molecular (genetic) biomarkers presented in this review will provide the foundation for future studies of the chemopreventive properties of structurally varied selenium compounds.
 ...
PMID:Molecular chemoprevention by selenium: a genomic approach. 1609 79

Redox modification of thiol/disulfide interchange in proteins by selenium could lead to protein unfolding. When this occurs in the endoplasmic reticulum (ER), a process known as unfolded protein response (UPR) is orchestrated for survival through activation of PERK-eIF2alpha (PERK: double-stranded RNA-activated protein kinase-like ER kinase; eIF2alpha: eucaryotic initiation factor 2alpha), ATFalpha (ATFalpha: activating transcription factor 6) and inositol requiring 1 (IRE1)-x-box-binding protein 1 (XBP1) signalings. All three UPR transducer pathways were upregulated very rapidly when PC-3 cells were exposed to selenium. These changes were accompanied by increased expression of UPR target genes, including immunoglobulin heavy chain-binding protein/glucose-regulated protein, 78 kDa and CCAAT/enhancer binding protein-homologous protein/growth arrest- and DNA damage-inducible gene (CHOP/GADD153). Induction of BiP/GRP78, an ER-resident chaperone, is part of the damage control mechanism, while CHOP/GADD153 is a transcription factor associated with growth arrest and apoptosis in the event of prolonged ER stress. Knocking down BiP/GRP78 induction by small interference RNA produced a differential response of the three transducers to selenium, suggesting that the signaling intensity of each transducer could be fine-tuned depending on BiP/GRP78 availability. In the presence of selenium, CHOP/GADD153 expression was raised even higher by BiP/GRP78 knockdown. Under this condition, the selenium effect on wild-type p53-activated fragment p21 (p21(WAF)), cyclin-dependent kinase (CDK)1 and CDK2 was also magnified in a manner consistent with enhanced cell growth arrest. Additional experiments with CHOP/GADD153 siRNA knockdown strongly suggested that CHOP/GADD153 may play a positive role in upregulating the expression of p21(WAF) in a p53-independent manner (PC-3 cells are p53 null). Collectively, the above findings support the idea that UPR could be an important mechanism in mediating the anticancer activity of selenium.
 ...
PMID:Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. 1620 45

Although the anticancer effects of selenium have been shown in clinical, preclinical, and laboratory studies, the underlying mechanism(s) remains unclear. Our previous study showed that sodium selenite induced LNCaP human prostate cancer cell apoptosis in association with production of reactive oxygen species, alteration of cell redox state, and mitochondrial damage. In the present study, we showed that selenite-induced apoptosis was superoxide mediated and p53 dependent via mitochondrial pathways. In addition, we also showed that superoxide production by selenite was p53 dependent. Our study showed that wild-type p53-expressing LNCaP cells were more sensitive to selenite-induced apoptosis than p53-null PC3 cells. Selenite treatment resulted in high levels of superoxide production in LNCaP cells but only low levels in PC3 cells. LNCaP cells also showed sequential increases in levels of phosphorylated p53 (serine 15), total p53, Bax, and p21(Waf1) proteins following selenite treatment. The effects of selenite were suppressed by pretreatment with a synthetic superoxide dismutase mimic or by knockdown of p53 via RNA interference. LNCaP cells treated with selenite also showed p53 translocation to mitochondria, cytochrome c release into the cytosol, and activation of caspase-9. On the other hand, restoration of wild-type p53 expression in PC3 cells increased cellular sensitivity to selenite and resulted in increased superoxide production, caspase-9 activation, and apoptosis following selenite treatment. These results suggest that selenite induces apoptosis by producing superoxide to activate p53 and to induce p53 mitochondrial translocation. Activation of p53 in turn synergistically enhances superoxide production and apoptosis induced by selenite.
 ...
PMID:Expression of p53 enhances selenite-induced superoxide production and apoptosis in human prostate cancer cells. 1648 34

Few studies have assessed potential effect modifications by polymorphisms of susceptibility genes on the association between selenium intake and esophageal squamous cell carcinoma (ESCC). We studied the joint effects of dietary selenium and the GSTP1 and p53 polymorphisms on ESCC risk in a population-based case-control study with 218 ESCC cases and 415 controls in Taixing City, China. Dietary selenium intake was estimated from a food frequency questionnaire with 97 food items. GSTP1 and p53 polymorphisms were detected by RFLP-PCR assays. Logistic regression analyses were done to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Reduced ESCC risk was observed among individuals in the highest quartile of dietary selenium intake (adjusted OR, 0.31; 95% CI, 0.13-0.70) with a dose-dependent gradient (P(trend) = 0.01). The p53 Pro/Pro genotype was associated with increased risk of ESCC compared with the Arg/Arg genotype (adjusted OR, 2.02; 95% CI, 1.19-3.42). When combined with selenium consumption, an obvious increased risk was observed among individuals with the p53 Pro/Pro or GSTP1 Ile/Ile genotype with adjusted ORs of 3.19 (95% CI, 1.74-5.84) and 1.90 (95% CI, 1.03-3.51), respectively. Among smokers and alcohol drinkers, elevation of ESCC risk was more prominent among p53 Pro/Pro individuals who consumed a low level of dietary selenium (adjusted OR, 3.59; 95% CI, 1.49-8.66 for smokers and 6.19; 95% CI, 1.83-20.9 for drinkers). Our study suggests that the effect of dietary selenium on the risk of ESCC may be modulated by tobacco smoking, alcohol drinking, and p53 Pro/Pro and GSTP1 Ile/Ile genotypes.
 ...
PMID:Dietary selenium intake and genetic polymorphisms of the GSTP1 and p53 genes on the risk of esophageal squamous cell carcinoma. 1649 18

Sodium selenite was used to examine whether selenium compound is able to trigger apoptotic degeneration in cultured cortical neurons in vitro and to explore the detailed changes in expression of the related genes during the apoptotic processes using molecular biological and flow cytometric examinations. The results indicated that: (1) cortical neurons treated with sodium selenite with different dosages (0.0008, 0.004, 0.0200, 0.1000, and 0.5000 microM) and different exposure times (2, 4, 24, and 48 h) exhibited dose- and time-dependent apoptotic processes as revealed by typical DNA ladder formation detected by agarose gel electrophoresis; (2) the internucleosomal DNA fragmentation detected by flow cytometric examination showed a prominent peak of hypodiploid DNA contents as early as 4h after exposure of 0.1 microM sodium selenite; (3) the DNA fragmentation induced by sodium selenite as revealed by the above two examinations could be blocked by aurintricarboxylic acid; (4) the transcriptions of mRNAs related to bcl-2, bax, c-fos, p53, and acetylcholinesterase (AChE) genes, as detected by RT-PCR assays, showed down-regulation for bcl-2 and up-regulation for bax, c-fos, p53, and AChE genes after exposure of sodium selenite. This study suggests that the sodium selenite is effective for inducing apoptosis in cultured cortical neurons and that relevant changes in expression of several apoptosis-related genes might further our understanding of the mechanism(s) that initiates and maintains the apoptotic processes.
 ...
PMID:Sodium selenite induces apoptosis in cultured cortical neurons with special concomitant changes in expression of the apoptosis-related genes. 1654 27

Dietary selenium has potent cancer prevention activity. Both low molecular weight selenocompounds and selenoproteins are implicated in this effect. Thioredoxin reductase 1 (TR1) is one of the major antioxidant and redox regulators in mammals that supports p53 function and other tumor suppressor activities. However, this selenium-containing oxidoreductase is also overexpressed in many malignant cells and has been proposed as a target for cancer therapy. To further assess the role of TR1 in the malignancy process, we used RNA interference technology to decrease its expression in mouse lung carcinoma (LLC1) cells. Stable transfection of LLC1 cells with a small interfering RNA construct that specifically targets TR1 removal manifested a reversal in the morphology and anchorage-independent growth properties of these cancer cells that made them similar to those of normal cells. The expression of at least two cancer-related protein mRNAs, Hgf and Opn1, were reduced dramatically in the TR1 knockdown cells. Mice injected with the TR1 knockdown showed a dramatic reduction in tumor progression and metastasis compared with those mice injected with the corresponding control vector. In addition, tumors that arose from injected TR1 knockdown cells lost the targeting construct, suggesting that TR1 is essential for tumor growth in mice. These observations provide direct evidence that the reduction of TR1 levels in malignant cells is antitumorigenic and suggest that the enzyme is a prime target for cancer therapy.
 ...
PMID:Thioredoxin reductase 1 deficiency reverses tumor phenotype and tumorigenicity of lung carcinoma cells. 1656 19

Selenium, in the form of seleno-L-methionine (SeMet), induced Redox-factor-1 (Ref1) and p53 proteins in normal human and mouse fibroblasts. Ref1 and p53 are known to be associated with each other, resulting in enhanced sequence-specific DNA binding by p53 and transactivation of p53-regulated effector genes. SeMet preferentially induced the DNA repair branch of the p53 pathway, while apoptosis and cell cycle arrest were unaffected. Accordingly, pretreatment with SeMet protected normal fibroblasts from subsequent DNA damage. In the current study, Brca1 and Ref1 were shown to interact concurrently with p53 in targeting a SeMet-induced DNA repair response. Moreover, like p53 and Ref1, Brca1 was required for SeMet-mediated DNA damage protection, as brca1 -/- mouse fibroblasts were not protected from UV-radiation by SeMet treatment. These findings indicate that besides p53 and Ref1, Brca1 is required for selenium protection from DNA damage. The data are consistent with selective induction of the DNA repair branch of the p53 pathway by SeMet.
 ...
PMID:Selenium protection from DNA damage involves a Ref1/p53/Brca1 protein complex. 1661 85

While there is an increasing interest in selenium chemoprevention against human colon polyp recurrence and other cancers, the mechanism(s) by which these agents inhibit carcinogenesis are uncertain. Some of the proposed mechanisms include the inhibition of cytosine methyltransferases, carcinogen bioactivation, and inhibition of cyclooxygenase (COX). More recently, it has been suggested that selenium may exert growth inhibitory effects by activating p53. However, the molecular mechanisms of action of selenomethionine, an organoselenium compound present in selenized yeast and currently being investigated in human clinical trials for colon polyp prevention, are unclear. In the present study we tested the hypothesis that selenomethionine might affect colon cancer cell growth by p53 mediated apoptosis and/or cell cycle regulation. Four human colon cancer cell lines including HCT116 and RKO (wild type p53), HCT116-p53KO (isogenic control of HCT116 cells with p53 knocked out) and Caco-2 (mutant p53) were treated with 0-100 microM of selenomethionine for 24, 48 and 72 h. Cell viability rates were determined by the MTT assay. Cell cycle analysis was performed by flow cytometry and apoptosis measured by Annexin V-Cy5 staining. Expression of p53 protein was determined by Western blotting and immunofluorescence assays. All cell lines showed concentration and time dependent growth inhibition with selenomethionine, although HCT116 and RKO cells were the most sensitive to such treatments. Interestingly, although HCT116 and HCT116-p53KO are isogenic cell lines, selenomethionine caused a G2/M cell cycle arrest in HCT116 and RKO cells, but not in HCT116-p53KO cells. Similarly, both HCT116 and RKO demonstrated a significant increase in apoptosis (100-170%; p < 0.01) with 50-100 microM selenomethionine. Cell cycle arrest and apoptosis observed in HCT116 and RKO cell lines were accompanied by a marked increase in p53 protein expression following selenium treatment. These results clearly suggest that selenomethionine exerts p53 dependent growth inhibitory effects in colon cancer cells by inducing G2/M cell cycle arrest as well as apoptosis.
 ...
PMID:Selenomethionine induces p53 mediated cell cycle arrest and apoptosis in human colon cancer cells. 1662 76

Selenium has been associated with cancer prevention. Despite vast knowledge of selenium effect on various health conditions, functional characterization of selenium metabolic enzymes on cellular physiology has been limited. Therefore, to gain insight into the mechanisms underlying cancer prevention by selenium, we investigated sps1, one of the two human selenophosphate synthetase genes for its role in cancer cell's response to ionizing radiation. Although stable expression of Sps1 protein per se had little effect on cell proliferation, concurrent irradiation decreased viability of the sps1 cell line. The increased sensitivity of the cell lines to ionizing radiation was correlated with increased p53 activity as well as with simultaneous up- and downregulation of Bax and Bcl2, respectively. Knockdown of sps1 and p53 by small interfering RNA method revealed that the level of p53 was proportional to that of Sps1 and that the increased radiosensitivity was dependent upon p53. Sps1 cell lines displayed decreased level of reactive oxygen species (ROS) with concomitant increase of certain redox enzymes. Furthermore, p53 activity was regulated by cellular redox via Ref1 in sps1 cell lines. Collectively, our results demonstrated that sps1 was able to affect cell viability upon ionizing radiation via modulation of p53 activity. They further suggest that Sps1 and its reaction product selenophosphate might be involved in cancer prevention in a p53-dependent manner and could be applied to development of a novel cancer therapy.
 ...
PMID:p53-Mediated enhancement of radiosensitivity by selenophosphate synthetase 1 overexpression. 1678 70


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>