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)

2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid, and it plays a critical role in cannabinoid receptor-mediated cell signaling. Although 2-AG was shown to induce ERK activation via the cannabinoid receptor 1 (CB1), only a nonspecific CB receptor agonist and antagonist was used in those studies. Whether cannabinoid receptor 2 (CB2) is involved in 2-AG-induced ERK activation is still unclear. Moreover, whether 2-AG is involved in mediation of AP-1 activity and cell transformation is also not known. In the present study, we show that 2-AG stimulates AP-1-dependent transcriptional activity and enhances epidermal growth factor-induced cell transformation in mouse epidermal JB6 P+ Cl41 cells. Using JB6 P+ C141 cells, stably transfected with an AP-1 luciferase reporter, we found that 10 microm 2-AG induced up to a 3-fold stimulation of AP-1 transcriptional activity. The AP-1 stimulation appeared to be mediated by ERK but not JNK or p38 kinase. PD98059, a specific inhibitor of MEK1, almost completely blocked 2-AG-induced ERK phosphorylation and AP-1 activation. Using CB1/2-/- murine embryonic fibroblasts, we present the first direct evidence that both cannabinoid receptors 1 and 2 (CB1/2) are involved in 2-AG-induced ERK activation. 2-AG could not stimulate ERK phosphorylation or Fyn kinase activity in dominant negative Fyn. In addition, the Fyn inhibitor PP2 blocked 2-AG-induced Fyn kinase activity and ERK phosphorylation and activity. Small interfering RNA Fyn also suppressed 2-AG-induced ERK phosphorylation. Interestingly, 2-AG enhanced epidermal growth factor-induced AP-1 DNA binding and cell transformation. Taken together, our data provide direct evidence suggesting that 2-AG may have a novel role in cell transformation and carcinogenesis in a signaling pathway involving CB1/2 and activation of Fyn, ERKs, and AP-1.
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PMID:2-Arachidonoylglycerol stimulates activator protein-1-dependent transcriptional activity and enhances epidermal growth factor-induced cell transformation in JB6 P+ cells. 1588 10

Although the dioxin receptor, the aryl hydrocarbon receptor (AhR), is considered a major regulator of xenobiotic-induced carcinogenesis, its role in tumor formation in the absence of xenobiotics is still largely unknown. Trying to address this question, we have produced immortalized cell lines from wild-type (T-FGM-AhR+/+) and mutant (T-FGM-AhR-/-) mouse mammary fibroblasts by stable co-transfection with the simian virus 40 (SV-40) large T antigen and proto-oncogenic c-H-Ras. Both cell lines had a myofibroblast phenotype and similar proliferation, doubling time, SV-40 and c-H-Ras expression and activity, and cell cycle distribution. AhR+/+ and AhR-/- cells were also equally able to support growth factor- and anchorage-independent proliferation. However, the ability of T-FGM-AhR-/- to induce subcutaneous tumors (leimyosarcomas) in NOD/SCID-immunodeficient mice was close to 4-fold lower than T-FGM-AhR+/+. In culture, T-FGM-AhR-/- had diminished migration in collagen-I and decreased lamellipodia formation. VEGFR-1/Flt-1, a VEGF receptor that regulates cell migration and blood vessel formation, was also down-regulated in AhR-/- cells. Signaling through the ERK-FAK-PKB/AKT-Rac-1 pathway, which contributes to cell motility and invasion, was also significantly inhibited in T-FGM-AhR-/-. Thus, the lower tumorigenic potential of T-FGM-AhR-/- could result from a compromised adaptability of these cells to the in vivo microenvironment, possibly because of an impaired ability to migrate and to respond to angiogenesis.
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PMID:Immortalized mouse mammary fibroblasts lacking dioxin receptor have impaired tumorigenicity in a subcutaneous mouse xenograft model. 1594 50

RTP801 is a newly discovered stress-response gene that is induced by hypoxia and other cell stress signals. Arsenic is a heavy metal that is linked to carcinogenesis in humans. Here, we investigated the mechanism by which arsenic induces RTP801 transcription. In HaCaT human keratinocytes, arsenite was able to induce a rapid rise in the RTP801 mRNA level. Correspondingly, arsenite treatment was capable of stimulating a 2.5 kb human RTP801 promoter. Such a stimulatory effect was inhibited by co-expression of superoxide dismutase or glutathione peroxidase, and was abrogated by N-acetylcysteine, implying that ROS (reactive oxygen species) were involved in transcriptional regulation of the RTP801 gene. A series of deletion studies with the promoter revealed a critical arsenic-responsive region between -1057 and -981 bp of the promoter. Point mutations of the putative Elk-1 site and the C/EBP (CCAAT/enhancer-binding protein) site within this region were able to reduce the stimulatory effect of arsenite, indicating that Elk-1 and C/EBP are involved in transcriptional regulation of the RTP801 gene by arsenite. Furthermore, a gel mobility-shift assay demonstrated that arsenite was able to mount the rapid formation of a protein complex that bound the arsenic-responsive region as well as the C/EBP-containing sequence. The arsenite stimulation on RTP801 transcription was partly mediated by the ERK (extracellular-signal-regulated kinase) pathway, since the effect of RTP801 was inhibited by a selective ERK inhibitor. In addition, overexpression of Elk-1 and C/EBPbeta was able to elevate the promoter activity. Therefore these studies indicate that RTP801 is a transcriptional target of arsenic in human keratinocytes, and that arsenic and ROS production are linked to Elk-1 and C/EBP in the transcriptional control.
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PMID:Arsenite induces a cell stress-response gene, RTP801, through reactive oxygen species and transcription factors Elk-1 and CCAAT/enhancer-binding protein. 1600 23

ped/pea-15 is a cytosolic protein performing a broad antiapoptotic function. We show that, upon DMBA/TPA-induced skin carcinogenesis, transgenic mice overexpressing ped/pea-15 (Tg(ped/pea-15)) display early development of papillomas and a four-fold increase in papilloma number compared to the nontransgenic littermates (P<0.001). The malignant conversion frequency was 24% for the Tg(ped/pea-15) mice and only 5% in controls (P<0.01). The isolated application of TPA, but not that of DMBA, was sufficient to reversibly upregulate ped/pea-15 in both untransformed skin and cultured keratinocytes. ped/pea-15 protein levels were also increased in DMBA/TPA-induced papillomas of both Tg(ped/pea-15) and control mice. Isolated TPA applications induced Caspase-3 activation and apoptosis in nontransformed mouse epidermal tissues. The induction of both Caspase-3 and apoptosis by TPA were four-fold inhibited in the skin of the Tg(ped/pea-15) compared to the nontransgenic mice, accompanied by a similarly sized reduction in TPA-induced JNK and p38 stimulation and by constitutive induction of cytoplasmic ERK activity in the transgenics. ped/pea-15 expression was stably increased in cell lines from DMBA/TPA-induced skin papillomas and carcinomas, paralleled by protection from TPA apoptosis. In the A5 spindle carcinoma cell line, antisense inhibition of ped/pea-15 expression simultaneously rescued sensitivity to TPA-induced Caspase-3 function and apoptosis. The antisense also reduced A5 cell ability to grow in semisolid media by 65% (P<0.001) and increased by three-fold tumor latency time (P<0.01). Thus, the expression levels of ped/pea-15 control Caspase-3 function and epidermal cell apoptosis in vivo and determine susceptibility to skin tumor development.
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PMID:Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development. 1604 59

The molecular mechanisms mediating arsenic-induced carcinogenesis are not well understood. The role of confounding factors such as ultraviolet radiation (UV), add another level of complexity to the study of arsenic carcinogenesis and the cancer-risk assessment on humans. We hypothesized that arsenicals are capable of overriding the growth arrest caused by UV treatment and may lead to selective proliferation. To test this hypothesis, a primary normal human epidermal keratinocyte (NHEK) cell culture model was used. One group was pre-exposed to UVB (100 mJ/cm(2)) that arrested a majority ( approximately 95%) of cells in G0/G1 (+UV) and a second group was not exposed to UV (-UV). Treatment of cells with various arsenicals [0-12 microM of inorganic arsenite (iAs), 0-2 microM of methyl oxoarsine (MMAs III) and 0-3 microM of iododimethyl arsine (DMAs III)] indicated a concentration-dependent increase in proliferation at 24 h in the order of DMAs III > MMAs III > iAs. Flow-cytometric analyses revealed differential effects on cell cycle distribution. Analysis of a battery of cell cycle proteins (cyclin D1, cdk5, PCNA, cdc25A and cdc25C) indicated exposure-specific differential expression profiles. Increased activation of JNK phosphorylation (5-10-fold) in the +UV group and the synergistic increase with methyl arsenicals suggested that JNK might be involved in cell survival and proliferative signaling. Induction of EGF levels and increased phosphorylation of the EGF receptor by arsenicals (+UV) suggested that the EGF signaling pathway might mediate arsenical-induced cell proliferation of NHEK cells. Differential activation of ERK1/2 by arsenicals (+/-UV) suggested that EGF-mediated cell proliferation by arsenicals in UV-treated NHEK cells may not involve ERK activation. Taken together, the data suggest that both UV exposure and methylation status of the arsenicals dictate the participation of key cell cycle proteins and related signaling events in arsenical-induced cell proliferation.
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PMID:The effect of arsenicals on ultraviolet-radiation-induced growth arrest and related signaling events in human keratinocytes. 1607 27

p66(Shc), an isoform of Shc adaptor proteins, is shown to mediate various signals, including cellular stress. However, little is known about its involvement in carcinogenesis. We previously showed that p66(Shc) protein level is upregulated by steroid hormones in human carcinoma cells and is higher in prostate cancer (PCa) specimens than adjacent noncancerous cells. In this study, we investigated the role of p66(Shc) protein in PCa cell proliferation. Among different PCa cell lines tested, p66(Shc) protein level showed positive correlation with cell proliferation, that is, rapid-growing cells expressed higher p66(Shc) protein than slow-growing cells. Exposure of slow-growing LNCaP C-33 cells to epidermal growth factor (EGF) and 5alpha-dihydrotestosterone (DHT) led to upregulation of proliferation and p66(Shc) protein level. Conversely, growth suppression of fast-growing cells by cellular form of prostatic acid phosphatase (cPAcP) expression, a negative growth regulator, down-regulated their p66(Shc) protein level. Additionally, increased expression of p66(Shc) protein by cDNA transfection in LNCaP C-33 cells resulted in increased cell proliferation. Cell cycle analyses showed higher percentage of p66(Shc)-overexpressing cells at S phase (24%) than control cells (17%), correlating with their growth rates. On the other hand, transient knock-down of p66(Shc) expression by RNAi in rapidly growing cells decreased their proliferation as evidenced by the reduced cell growth as well as S phase in p66(Shc)-knocked down cells. The p66(Shc) signaling in cell growth regulation is apparently mediated by extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK). Thus, our results indicate a novel role for p66(Shc) in prostate carcinogenesis, in part, promoting cell proliferation.
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PMID:Expression of p66(Shc) protein correlates with proliferation of human prostate cancer cells. 1617 Mar 80

It was originally shown by Woerner and Schrenk [Woerner, W., Schrenk, D., 1998. 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses apoptosis and leads to hyperphosphorylation of p53 in rat hepatocytes. Environ. Toxicol. Pharmacol. 6, 239-247] that TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) acts as an antagonist against the action of UV-irradiation to induce apoptosis in rat primary hepatocytes. Since prevention of apoptosis has been shown to promote carcinogenesis, we have decided to investigate this phenomenon in a human mammary gland epithelial cell line, MCF10A. We found that, in this cell line, TCDD can antagonize apoptosis that was induced by a variety of treatments, such as UV- and gamma-irradiation, growth factor starvation and trypsinization, or by the addition of H(2)O(2), TGFbeta, and staurosporine. Furthermore, other agents that are known to elicit defensive cellular responses, such as LPS, Fe(3+), nitric oxide and hypoxia could also antagonize UV induced apoptosis just as in the case of TCDD. In addition, we found that, in this cell line, such anti-apoptotic action of TCDD resembles that of exogenously added EGF or TGF alpha. To study the basic mechanism of such an action of TCDD, we tested a variety of diagnostic agents to reverse the effect of TCDD. Antagonists of TCDD which were found to be effective in this way were (a) inhibitors of c-Src kinase, such as PP-2 and CGP77675, (b) those known to block the action of TGF alpha, such as anti-TGF alpha antibody, and alpha(1)-antitrypsin, (c) PD98059, a specific inhibitor of ERK activation, but not SB202190 (an inhibitor of p38 MAPK activation) or SP600125 (a JNK inhibitor) and (d) Ah receptor antagonists, alpha-naphthoflavone and 1, 10-phenanthroline. These results support the notion that TCDD acts as an anti-apoptotic agent by mimicking the action of EGF through activation of the c-Src/ERK signaling pathway.
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PMID:Characterization of anti-apoptotic action of TCDD as a defensive cellular stress response reaction against the cell damaging action of ultra-violet irradiation in an immortalized normal human mammary epithelial cell line, MCF10A. 1621 48

We have found previously that human plasma-membrane-associated sialidase (NEU3), a key glycosidase for ganglioside degradation, was markedly up-regulated in human colon cancers, with an involvement in suppression of apoptosis. To elucidate the molecular mechanisms underlying increased NEU3 expression, in the present study we investigated its role in cell adhesion of human colon cancer cells. DLD-1 cells transfected with NEU3 exhibited increased adhesion to laminins and consequent cell proliferation, but decreased cell adhesion to fibronectin and collagens I and IV, compared with control cells. When triggered by laminins, NEU3 clearly stimulated phosphorylation of FAK (focal adhesion kinase) and ERK (extracellular-signal-regulated kinase), whereas there was no activation on fibronectin. NEU3 markedly enhanced tyrosine phosphorylation of integrin beta4 with recruitment of Shc and Grb-2 only on laminin-5, and NEU3 was co-immunoprecipitated by an anti-(integrin beta4) antibody, suggesting that association of NEU3 with integrin beta4 might facilitate promotion of the integrin-derived signalling on laminin-5. In addition, the promotion of phosphorylation of integrin beta1 and ILK (integrin-linked kinase) was also observed on laminins. G(M3) depletion as the result of NEU3 overexpression, assessed by TLC, appeared to be one of the causes of the increased adhesion on laminins and, in contrast, of the decreased adhesion on fibronectin - NEU3 probably having bimodal effects. These results indicate that NEU3 differentially regulates cell proliferation through integrin-mediated signalling depending on the extracellular matrix and, on laminins, NEU3 did indeed activate molecules often up-regulated in carcinogenesis, which may cause an acceleration of the malignant phenotype in cancer cells.
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PMID:Plasma-membrane-associated sialidase (NEU3) differentially regulates integrin-mediated cell proliferation through laminin- and fibronectin-derived signalling. 1624 5

The Ras-Raf-MAPK pathway has been implicated in lung carcinogenesis and, potentially, the maintenance of the malignant phenotype in these tumors. Mutations in ras and B-raf genes have been described in lung cancer, representing one of the few examples of tandem mutations in a signaling cascade. As a result, numerous approaches to inhibiting this pathway in lung cancer have been explored in the past decade. The most promising approach to date appears to be the inhibition of mitogen-activated ERK kinase or MEK. In this review, the potential utility of MEK inhibitors in the therapy of lung cancer is discussed.
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PMID:The role of mitogen-activated ERK-kinase inhibitors in lung cancer therapy. 1635 19

To test the hypothesis that suppression of ornithine decarboxylase (ODC) activity blocks the promotion of target cells in the outer root sheath of the hair follicle initiated by Raf/MEK/ERK activation, we crossed mice overexpressing an activated MEK mutant in the skin (K14-MEK mice) with two transgenic lines overexpressing antizyme (AZ), which binds to ODC and targets it for degradation. K14-MEK mice develop spontaneous skin tumors without initiation or promotion. These mice on the ICR background were crossed with K5-AZ and K6-AZ mice on both the carcinogenesis-resistant C57BL/6 background and the sensitive DBA/2 background. Expression of AZ driven by either the K5 or K6 promoter along with K14-MEK dramatically delayed tumor incidence and reduced tumor multiplicity on both backgrounds compared with littermates expressing the MEK transgene alone. The effect was most remarkable in the MEK/K6-AZ mice from the ICR/D2 F1 cross, where double transgenic mice averaged less than one tumor per mouse for more than 8 weeks, while K14-MEK mice averaged over 13 tumors per mouse at this age. Putrescine was decreased in MEK/AZ tumors, while spermidine and spermine levels were unaffected, suggesting that the primary role played by AZ in this system is to inhibit putrescine accumulation. MEK/AZ tumors did not show evidence of apoptosis, but there was a 15-20% decrease in S-phase cells and a 40-60% decrease in mitotic cells in MEK/AZ tumors. These results indicate that the principal effect of AZ may be to slow cell growth primarily by increasing G2/M transit time.
Carcinogenesis 2006 May
PMID:Tumor suppressor activity of ODC antizyme in MEK-driven skin tumorigenesis. 1640 Jan 86


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