Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Butyrate, one of the major products of gut fermentation, is known to inhibit proliferation, induce apoptosis and differentiation, and increase phase II enzyme activities in tumor cells, whereas little information is available on protective effects in less-transformed colon cells. The aim of this study was to investigate whether the chemoprotective mechanism of glutathione S-transferase (GST) induction by butyrate could also play a role in earlier stages of colon carcinogenesis and whether chemoresistance of cells toward the endogenous genotoxic risk factor 4-hydroxy-2-nonenal (HNE) could be a consequence of butyrate treatment. As cell models, we used the human tumor cell lines HT29 and HT29 clone 19A, a differentiated subclone with properties resembling primary colon cells. We determined the expression of GSTP1 protein (enzyme-linked immunosorbent assay), the major GST in HT29, GSTP1 mRNA (Northern blotting), GST activity, intracellular glutathione, and total protein. The genotoxic impact of HNE (100-200 microM) was compared in butyrate-treated and nontreated cells using single-cell microgel electrophoresis. Our results show that GSTP1 mRNA, GSTP1 protein, GST activity, and total protein were increased (1.2- to 2.5-fold) and glutathione levels were maintained after 24-72 h of incubation with 4 mM butyrate. Moreover, a marked reduction of HNE-induced genotoxicity was caused by preincubation with butyrate. Butyrate also induced the phosphorylation of extracellular signal-regulated kinases (ERK1/2, Western blotting) after 5-30 min, which indicates a regulation of GST expression by this signal pathway. Most effects were greater in HT29 parent cells than in clone cells. In conclusion, butyrate enhances expression of GST and other proteins in both cell lines, which leads to an enhanced chemoprotection, reducing the impact of HNE genotoxicity. Thus butyrate could play a role in early and later stages of cancer prevention by reducing exposure to relevant risk factors.
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PMID:Butyrate induces glutathione S-transferase in human colon cells and protects from genetic damage by 4-hydroxy-2-nonenal. 1209 19

Modulation of gap junctional intercellular communication (GJIC) is a known cellular event associated with tumor promotion. The present study was undertaken to test the potential preventive effect of mushroom Phellinus linteus extract (PL) on the inhibition of GJIC, induced by hydrogen peroxide (H(2)O(2)), in WB-F344 rat liver epithelial cells (WB cells). Cells were pre-incubated with PL (5 and 25 microg/ml) for 24 h and this was followed by co-treatment with PL and H(2)O(2) (500 microM) for 1 h. PL (at 5 and 25 microg/ml) prevented the inhibition of GJIC and blocked the hyper-phosphorylation of connexin 43 by H(2)O(2). Moreover, H(2)O(2) activated p38 kinase, extracellular signal-regulated protein kinases (ERK)1/2 and c-Jun N-terminal kinase (JNK) in WB cells. The present study indicates that PL is able to inactivate both ERK1/2 and p38 MAP kinases. However, PL did not affect the JNK pathway. For this reason, to elucidate the relation between MAP kinases and GJIC, we treated cells with PD98059 (an MEK inhibitor) and SB202190 (a p38 kinase inhibitor). These inhibitors were also found to prevent the inhibition of GJIC induced by H(2)O(2), which suggests that PL may act as a natural anticancer product by preventing the inhibition of GJIC through the inactivation of ERK1/2 and p38 MAP kinases. In addition, our results indicate that the p38 kinase signaling pathway may be closely related functionally to the gap junction in rat liver epithelial cells.
Carcinogenesis 2002 Jul
PMID:The roles of ERK1/2 and p38 MAP kinases in the preventive mechanisms of mushroom Phellinus linteus against the inhibition of gap junctional intercellular communication by hydrogen peroxide. 1211 74

Reg is a growth factor with mitogenic effects on pancreatic beta cells and gastric stem cells. To date, there has been no information available on Reg-mediated intracellular signal transduction pathways. The role of Reg in the gastric carcinogenesis is also unknown. In the current study, the Reg signaling pathway in gastric cancer cell was examined. Reg treatment of MKN45 gastric cancer cells resulted in tyrosyl-phoshorylation of several cellular proteins and subsequent activation of classical MAPK, ERK1/2. Reg also stimulated thymidine incorporation in MKN45 and AGS gastric cancer cells in a dose-dependent manner. Finally, Reg was shown to be highly expressed in a large number of gastric cancers in vivo. Taken together, these data suggest that gastric cancer cells have gained the ability to overexpress Reg protein, which confer upon themselves added proliferative capacities, resulting in a considerable growth advantage.
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PMID:Reg protein is overexpressed in gastric cancer cells, where it activates a signal transduction pathway that converges on ERK1/2 to stimulate growth. 1457 70

Genistein (4',5,7-trihydroxyisoflavone) is an isoflavonoid present in soybeans that exhibits anticarcinogenic effects in breast, colon and prostate cancer cells. We recently reported that genistein treatment of the immortalized but nonmalignant human mammary epithelial cell line MCF-10F resulted in growth arrest of MCF-10F cells in the G2 phase of the cell cycle, a large induction of the Tyr15 phosphorylation of Cdc2 (along with decreased activity of Cdc2), increased expression of p21(waf/cip1) and decreased expression of the cell cycle phosphatase Cdc25C. In the present study of MCF-10F cells, genistein rapidly and significantly activated p38, inactivated ERK1/ERK2 and had no effect on SAPK/JNK activity. We also showed that p38 is involved in genistein-induced changes in Cdc2 phosphorylation and that the downregulation of Cdc25C expression by genistein is through the p38 pathway. Finally, we provided evidence that the p38 pathway is involved in genistein-inhibited cell proliferation. These data suggest an important interplay between the p38 pathway and G2 cell cycle checkpoint control and provide insights into possible mechanisms whereby this isoflavone may inhibit early events in mammary carcinogenesis.
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PMID:Genistein activates p38 mitogen-activated protein kinase, inactivates ERK1/ERK2 and decreases Cdc25C expression in immortalized human mammary epithelial cells. 1251 95

Lead, a possible human carcinogen, affects signal transduction pathways in many aspects, yet exhibits low mutagenicity in human cells. In this study, we explore whether signaling pathways including the four MAPKs and AKT affect DNA repair and mutagenicity in the exposure of mammalian cells to lead acetate [Pb(II)]. Pb(II) increased the phosphorylated ERK1/2 and phosphorylated AKT but not the phosphorylated ERK5, phosphorylated p38 and JNK activity in human non-small cell lung adenocarcinoma CL3 cells. The duration of ERK1/2 activation was much longer than AKT activation and these two signals were independently activated by Pb(II) in CL3 cells. Intriguingly, a MKK1/2 inhibitor PD98059 (25-50 micro M) markedly suppressed ERK1/2 activation and greatly promoted the hprt mutation frequency and cytotoxicity in Pb(II)-treated CL3 cells. Conversely, inhibition of the AKT signal by wortmannin did not exhibit such effects. Inhibition of the persistently activated ERK1/2 in Pb(II)-treated diploid human fibroblasts by PD98059 also markedly increased the mutagenicity and cytotoxicity. The Pb(II)-induced mutagenicity and cytotoxicity were significantly higher in nucleotide excision repair (NER)-deficient UVL-10 rodent cells than their counterpart AT3-2 cells; also, ERK1/2 activation by Pb(II) was observed in AT3-2 but not UVL-10 cells. Furthermore, cellular NER synthesis was enhanced by Pb(II) exposure, which was markedly suppressed by PD98059. Activation of ERK1/2 by expressing a constitutively active form of MKK1 in CL3 cells also elevated cellular NER synthesis. Together, these results indicate that persistent activation of ERK1/2 signaling by Pb(II) enhances cellular NER synthesis, thereby conferring anti-cytotoxicity and anti-mutagenicity.
Carcinogenesis 2003 Jan
PMID:Persistent activation of ERK1/2 by lead acetate increases nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity. 1253 49

Resveratrol is a plant polyphenol found in grapes and red wine. It has been found to have beneficial effects on the cardiovascular system. Resveratrol also inhibits the growth of various tumor cell lines in vitro and inhibits carcinogenesis in vivo. In this study we examined the effect of resveratrol on growth of two human melanoma cell lines. We found that this plant polyphenol inhibited growth and induced apoptosis in both cell lines, with the amelanotic cell line A375 being more sensitive. The potential involvement of different MAP kinases in the action of resveratrol was also examined. Although resveratrol did not alter the phosphorylation of p38 or JNK MAP kinases in either cell line, it induced phosphorylation of ERK1/2 in A375, but not in SK-mel28 cells. These results suggest that in vivo studies of the effect of resveratrol on melanoma are warranted and that this plant polyphenol might have effectiveness as either a therapeutic or chemopreventive agent against melanoma.
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PMID:Resveratrol is a potent inducer of apoptosis in human melanoma cells. 1256 70

Because of similarities in histopathology and tumor progression stages between mouse and human lung adenocarcinomas, the mouse lung tumor model with lung adenomas as the endpoint has been used extensively to evaluate the efficacy of putative lung cancer chemopreventive agents. In this study, a competitive cDNA library screening (CCLS) was employed to determine changes in the expression of mRNA in chemically induced lung adenomas compared with paired normal lung tissues. A total of 2555 clones having altered expression in tumors were observed following competitive hybridization between normal lung and lung adenomas after primary screening of over 160,000 clones from a mouse lung cDNA library. Among the 755 clones confirmed by dot blot hybridization, 240 clones were underexpressed, whereas 515 clones were overexpressed in tumors. Sixty-five clones with the most frequently altered expression in six individual tumors were confirmed by semiquantitative RT-PCR. When examining the 58 known genes, 39 clones had increased expression and 19 had decreased expression, whereas the 7 novel genes showed overexpression. A high percentage (>60%) of overexpressed or underexpressed genes was observed in at least two or three of the lesions. Reproducibly overexpressed genes included ERK-1, JAK-1, surfactant proteins A, B, and C, NFAT1, alpha-1 protease inhibitor, helix-loop-helix ubiquitous kinase (CHUK), alpha-adaptin, alpha-1 PI2, thioether S-methyltransferase, and CYP2C40. Reproducibly underexpressed genes included paroxanase, ALDH II, CC10, von Ebner salivary gland protein, and alpha- and beta-globin. In addition, CCLS identified several novel genes or genes not previously associated with lung carcinogenesis, including a hypothetical protein (FLJ11240) and a guanine nucleotide exchange factor homologue. This study shows the efficacy of this methodology for identifying genes with altered expression. These genes may prove to be helpful in our understanding of the genetic basis of lung carcinogenesis and in developing biomarkers for lung cancer chemoprevention studies in mice.
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PMID:Differential gene expression in chemically induced mouse lung adenomas. 1265 69

Dual specificity phosphatases (DSP) play an important role in control of the cell cycle and signal transduction. We have synthesized a new class of DSP inhibitors. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent of these. It inhibits DSPs of cells in culture and induces tyrosine phosphorylation of various DSP substrates, including the Cdc25 target Cdks and it potently inhibits cell growth. In this study, we have evaluated Cpd 5 in vivo for its antitumor and growth inhibitory activity on carcinogen-altered foci. Cpd 5 inhibited growth of the transplantable rat hepatoma cell line JM-1 in vitro, with concomitant phosphorylation of the mitogen-activated protein kinase ERK1/2 but not JNK1/2 or p38. This ERK phosphorylation was associated with growth inhibition, as the ERK phosphorylation inhibitor PD098059 antagonized both ERK phosphorylation and growth inhibition. JM-1 cell lysates were found to contain ERK1/2-specific phosphatase(s) that could be inhibited by Cpd 5 and which are thought to be its major targets. Cpd 5 caused significant inhibition of both intrahepatic and subcutaneous (s.c.) growth of transplanted JM-1 cells in male Fischer F344 rats. The treatment was equally effective whether Cpd 5 was administered either as a single, acute dose or chronically as several lower doses. However, toxicity was much lower with chronic treatment. As in JM-1 cells in vitro, ERK1/2 was phosphorylated when rats in vivo were treated with Cpd 5 and tumor growth inhibition in vivo also was antagonized by treating rats with the ERK1/2 phosphorylation inhibitor PD098059. A single dose of Cpd 5 also inhibited the formation of glutathione S-transferase-pi enzyme-altered cells induced by the hepatocarcinogen N-nitrosodiethylamine. This is the first report of the in vivo activity and growth inhibitory mechanism of a novel class of K vitamin growth inhibitors that have potent tyrosine phosphatase activity.
Carcinogenesis 2003 Mar
PMID:Antitumor and anticarcinogenic actions of Cpd 5: a new class of protein phosphatase inhibitor. 1266 99

Mutational activation of beta-catenin and cyclin D1 over-expression are a frequent change in mouse hepatic tumors. Although activated beta-catenin may bind to T cell factor (TCF) family members and transcriptionally activate the cyclin D1 gene, either beta-catenin or cyclin D1 may be activated by various pathways independently of beta-catenin mutations. In this study, we investigated beta-catenin activation and mutations, cyclin D1 expression, H-ras mutations and phosphorylation of extracellular signal regulated protein kinases 1/2 (ERK1/2), Akt and glycogen synthetase kinase 3beta (GSK3 beta) in mouse hepatic carcinogenesis. Nuclear/cytoplasmic staining of beta-catenin, a sign of beta-catenin activation, was frequently observed in association with the high nuclear cyclin D1 labeling index in the hepatic tumors at the late stage of carcinogenesis. The beta-catenin activation was further suggested by the fact that all hepatocellular carcinoma (HCC) cell lines examined showed the nuclear beta-catenin/TCF4 complex together with cyclin D1 over-expression. However, the fact that only 31.8% (7/22) of the lesions with the nuclear/cytoplasmic beta-catenin staining showed beta-catenin mutations indicated that beta-catenin was activated not only by its own mutations but also by other reason(s). On the other hand, there was no correlation between the beta-catenin/cyclin D1 activation and the H-ras mutations or phosphorylation of Akt, GSK3 beta and ERK1/2, although GSK3 beta was frequently over-expressed in the tumors. These results indicate that, although beta-catenin and cyclin D1 activation are well correlated, the Akt/GSK3 beta and ras/ERK1/2 pathways may not play a major role in the beta-catenin/cyclin D1 activation.
Carcinogenesis 2003 Mar
PMID:Cyclin D1 over-expression correlates with beta-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3 beta and ERK1/2 in mouse hepatic carcinogenesis. 1266 2

The induction of glutathione S-transferases by flavonoids is associated with cancer chemopreventive effects. We reported that 2'-amino-3'-methoxyflavone (PD98059), an MKK1 inhibitor, induces glutathione S-transferase A2 (rGSTA2). This report comparatively examines the role of CCAAT/enhancer-binding protein (C/EBP) and Nrf2 in the induction of rGSTA2 by PD98059. We first assessed whether the MKK1/ERK1/2 pathway regulated rGSTA2 induction. Northern and western blot analyses showed that PD98059 at the concentrations effective for the inhibition of MKK1 increased the rGSTA2 protein and mRNA levels in H4IIE cells. PD98059 also induced rGSTA2 in cells stably transfected with dominant-negative mutant of MKK1(-), which provided evidence that the inhibition of MKK1/ERK1/2 by PD98059 was not responsible for rGSTA2 induction. Gel shift assay and immunoblot analysis of subcellular fractions revealed that PD98059 caused nuclear translocation of C/EBP beta and increased C/EBP DNA binding, which was super-shifted with anti-C/EBP beta antibody. Nrf2 was not activated by PD98059. PD98059 increased the luciferase reporter gene activity in cells transfected with the C/EBP-containing -1.65 kb flanking region of the rGSTA2 gene. Deletion of the C/EBP-binding site or over-expression of dominant-negative mutant of C/EBP abolished the reporter gene activity. Flavone, a backbone structure of PD98059, also induced nuclear translocation of C/EBP beta and C/EBP-mediated rGSTA2 gene induction. Inhibition of phosphatidylinositol 3-kinase abolished C/EBP beta-mediated rGSTA2 induction by PD98059. These results provide evidence that PD98059 and flavone induce nuclear translocation of C/EBP beta and activate the C/EBP-binding site in the rGSTA2 gene, which constitutes the distinct pathway for the enzyme induction irrespective of the inhibition of MKK1/ERK activity.
Carcinogenesis 2003 Mar
PMID:Activation of CCAAT/enhancer-binding protein beta by 2'-amino-3'-methoxyflavone (PD98059) leads to the induction of glutathione S-transferase A2. 1266 7


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