Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivation of tumor suppressor genes like p53 and p16 play a key role in tumor progression, with a high incidence of mutations existing for both genes in oral squamous cell carcinomas. Previous studies have demonstrated, (i) a correlation between the prevalence of p53 mutations and tobacco use [Brennan et al. (1995) New Engl. J. Med., 332, 712-717; Lazarus et al. (1996) Carcinogenesis, 17, 733-739], and (ii) a link between genotypes in specific xenobiotic metabolizing enzymes and oral cancer susceptibility [Park et al. (1997) Cancer Epid. Biomarkers Prev., 6, 791-797). In this paper, we present results of our examination of a series of 80 oral squamous cell carcinomas for p53 exons 5-9 and p16 exons 1-2 mutations, and the potential association of these mutations with specific genotyping patterns. p53 mutation prevalence in oral tumors was linked with increased patient tobacco use using several stratification criteria. There was a significantly higher prevalence of p53 mutations in OCSCCs from patients who smoked > 30 pack-years as compared to tumors from patients who smoked < or = 30 pack-years (OR = 2.8; CI = 1.1-7.2). No significant association was observed with patient alcohol consumption. There was a significant association between the prevalence of p53 mutations in oral tumors and CYP1A1 genotyping patterns in these oral cancer patients, with the highest p53 mutation prevalence observed in subjects with the CYP1A1 [val]/GSTM1 [+] genotype (OR = 6.0; CI = 1.2-29.7). A significant association was not observed between the prevalence of p16 mutations in oral tumors and tobacco use, or CYP1A1 [val] or GSTM1 (0/0) genotypes. These data suggest that the induction of mutations in specific tumor suppressor genes or oncogenes in oral tumors may be associated with specific carcinogen exposures, and that this association may be linked to specific polymorphic genotypes in xenobiotic-metabolizing enzyme genes.
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PMID:p53, but not p16 mutations in oral squamous cell carcinomas are associated with specific CYP1A1 and GSTM1 polymorphic genotypes and patient tobacco use. 952 87

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor composed of HIF-1alpha and HIF-1beta subunits. HIF-1 expression is induced by hypoxia, growth factors, and activation of oncogenes. HIF-1 activates downstream target genes such as vascular endothelial growth factor A (VEGF-A), which plays an important role in tumor progression and angiogenesis. Estrogen exposure is considered to be the major risk factor for ovarian cancer. Estradiol (E2) is usually metabolized by CYP1A1/1A2 and CYP3A4 to the 2-hydroxy estradiol (2-OHE2) and 4-hydroxy estradiol (4-OHE2) in human liver. Many reports have suggested that the formation of 4-OHE2 is important for mammary carcinogenesis. However, the formation of 2-OHE2 may play an important role in exhibiting anticarcinogenic effects. In the present study, we have demonstrated that one of the catechol estrogen metabolites of E2, 4-OHE2, induces HIF-1alpha and VEGF-A expression at protein level in two human ovarian cancer cell lines, OVCAR-3 and A2780-CP70 cells, in dose- and time-dependent manners, whereas the other catechol estrogen metabolite of E2, 2-OHE2, does not alter HIF-1alpha and VEGF-A expression. To explore the mechanism of 4-OHE2-induced HIF-1alpha and VEGF-A expression, we studied whether phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase (MAPK) signaling pathways are involved in 4-OHE2-induced HIF-1alpha and VEGF-A expression. Our findings indicate that PI3K inhibitors, LY294002 and wortmannin, inhibited HIF-1alpha and VEGF-A expression, whereas MAPK inhibitor, PD98059, did not alter HIF-1alpha and VEGF-A expression induced by 4-OHE2. 4-OHE2, but not 2-OHE2, also induced Akt phosphorylation at Ser473 in dose- and time-dependent manners, and LY294002 and wortmannin inhibited Akt phosphorylation at Ser473 induced by 4-OHE2. Our results also indicated that the mTOR/FRAP inhibitor, rapamycin, inhibited 4-OHE2-induced HIF-1alpha and VEGF-A expression. These results suggest that the PI3K/Akt/FRAP signaling pathway is required for HIF-1alpha and VEGF-A expression induced by 4-OHE2, whereas the MAPK pathway is not required. The finding that induction of HIF-1alpha and VEGF-A expression occurs via the activation of the PI3K/Akt/FRAP signaling pathway could be an important mechanism of 4-OHE2-induced carcinogenesis.
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PMID:4-Hydroxy estradiol but not 2-hydroxy estradiol induces expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor A through phosphatidylinositol 3-kinase/Akt/FRAP pathway in OVCAR-3 and A2780-CP70 human ovarian carcinoma cells. 1505 Apr 14

The potential to metabolize endogenous and exogenous substances may influence breast cancer development and tumor growth. Therefore, the authors investigated the protein expression of Glutathione S-transferase (GST) isoforms and cytochrome P450 (CYP) known to be involved in the metabolism of steroid hormones and endogenous as well as exogenous carcinogens in breast cancer tissue to obtain new information on their possible role in tumor progression. Expression of GST pi, mu, alpha and CYP1A1/2, 1A2, 3A4/5, 1B1, 2E1 was assessed by immunohistochemistry for primary breast carcinomas of 393 patients from the German GENICA breast cancer collection. The percentages of positive tumors were 50.1 and 44.5% for GST mu and CYP2E1, and ranged from 13 to 24.7% for CYP1A2, GST pi, CYP1A1/2, CYP3A4/5, CYP1B1. GST alpha was expressed in 1.8% of tumors. The authors observed the following associations between strong protein expression and histopathological characteristics: GST expression was associated with a better tumor differentiation (GST mu, p = 0.018) and with reduced lymph node metastasis (GST pi, p = 0.02). In addition, GST mu expression was associated with a positive estrogen receptor and progesterone receptor status (p < 0.001). CYP3A4/5 expression was associated with a positive nodal status (p = 0.018). Expression of CYP1B1 was associated with poor tumor differentiation (p = 0.049). Our results demonstrate that the majority of breast carcinomas expressed xenobiotic and drug metabolizing enzymes. They particularly suggest that GST mu and pi expression may indicate a better prognosis and that strong CYP3A4/5 and CYP1B1 expression may be key features of nonfavourable prognosis.
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PMID:Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas. 1672 11

The aryl hydrocarbon receptor (AhR) mediates transcriptional effects of a diverse array of ligands including environmental contaminants that have been linked to various cancers. The transcriptional activity of the AhR is modulated by different coregulators such as the p160 family members of coactivators and nuclear receptor coactivator 4 (NcoA4). In this study, we provide novel evidence that four and a half LIM only protein 2 (FHL2) interacts with and differentially modulates the transcriptional activity of AhR. Co-immunoprecipitation studies indicate that FHL2 interacts with AhR in a ligand-independent manner but not with its heterodimeric partner, AhR nuclear translocator (ARNT). Overexpression of FHL2 enhanced AhR-mediated expression of a luciferase reporter gene in a dose- and ligand-dependent manner in COS cells. Furthermore, FHL2 cooperated with NcoA4 to synergistically enhance AhR transcriptional activity in these cells. However, the impact of FHL2 on AhR transcriptional activity was cell-specific: FHL2 facilitated AhR action in MCF-7 and PC-3 cells, whereas it suppressed AhR activity in T47D and LNCaP cells. These results of reporter gene studies were corroborated by the impact of FHL2 overexpression on, an established target gene of AhR, cytochrome P450 (CYP1A1) expression. We also demonstrated a potential competition of AhR and androgen receptor (AR) for FHL2 availability in COS cells, as FHL2-facilitation was significantly decreased in the presence of liganded AR. These findings indicate a functional interaction between AhR and FHL2 that modulates the activity of AhR and therefore could affect its role in cancer progression or development.
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PMID:Modulation of aryl hydrocarbon receptor activity by four and a half LIM domain 2. 1901 43

Head and neck squamous cell carcinoma (HNSCC) is associated with environmental factors, especially tobacco and alcohol consumption. Most of the carcinogens present in tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 (CYPs) enzymes and detoxification of these substances is performed by glutathione S-transferases (GSTs). It has been suggested that genetic alterations, such as polymorphisms, play an important role in tumorigenesis and HNSCC progression. The aim of this study was to investigate CYP1A1, CYP1A2, CYP2E1, GSTM1, and GSTT1 polymorphisms as risk factors in HNSCC and their association with clinicopathologic data. The patients comprised 153 individuals with HNSCC (cases) and 145 with no current or previous diagnosis of cancer (controls). Genotyping of the single nucleotide polymorphisms (SNPs) of the CYP1A1, CYP1A2, and CYP2E1 genes was performed by PCR-RFLP and the GSTM1 and GSTT1 copy number polymorphisms (CNPs) were analyzed by PCR-multiplex. As expected, a significant difference was detected for tobacco and alcohol consumption between cases and controls (P<0.001). It was observed that the CYP1A2*1D (OR=16.24) variant and GSTM1 null alleles (OR=0.02) confer increased risk of HNSCC development (P<0.001). In addition, head and neck cancer alcohol consumers were more frequently associated with the CYP2E1*5B variant allele than control alcohol users (P<0.0001, OR=190.6). The CYP1A2*1C polymorphism was associated with tumor recurrence (log-rank test, P=0.0161). The CYP2E1*5B and GSTM1 null alleles were significantly associated with advanced clinical stages (T3+T4; P=0.022 and P=0.028, respectively). Overall, the findings suggested that the genetic polymorphisms studied are predictors of risk and are also associated with tumor recurrence, since they are important for determining the parameters associated with tumor progression and poor outcomes in HNSCC.
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PMID:CYP1A2*1C, CYP2E1*5B, and GSTM1 polymorphisms are predictors of risk and poor outcome in head and neck squamous cell carcinoma patients. 1944 64

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism.
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PMID:Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention. 1953 Dec 41

Inflammatory signaling plays a key role in tumor progression, and the pleiotropic cytokine interleukin-6 (IL-6) is an important mediator of protumorigenic properties. Activation of the aryl hydrocarbon receptor (AHR) with exogenous ligands coupled with inflammatory signals can lead to synergistic induction of IL6 expression in tumor cells. Whether there are endogenous AHR ligands that can mediate IL6 production remains to be established. The indoleamine-2,3-dioxygenase pathway is a tryptophan oxidation pathway that is involved in controlling immune tolerance, which also aids in tumor escape. We screened the metabolites of this pathway for their ability to activate the AHR; results revealed that kynurenic acid (KA) is an efficient agonist for the human AHR. Structure-activity studies further indicate that the carboxylic acid group is required for significant agonist activity. KA is capable of inducing CYP1A1 messenger RNA levels in HepG2 cells and inducing CYP1A-mediated metabolism in primary human hepatocytes. In a human dioxin response element-driven stable reporter cell line, the EC(25) was observed to be 104nM, while in a mouse stable reporter cell line, the EC(25) was 10muM. AHR ligand competition binding assays revealed that KA is a ligand for the AHR. Treatment of MCF-7 cells with interleukin-1beta and a physiologically relevant concentration of KA (e.g., 100nM) leads to induction of IL6 expression that is largely dependent on AHR expression. Our findings have established that KA is a potent AHR endogenous ligand that can induce IL6 production and xenobiotic metabolism in cells at physiologically relevant concentrations.
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PMID:Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. 2010 48

Trichloroethylene (TCE) is major industrial pollutant that contaminate environment. Its exposure may lead to hepato-renal toxicity along with the cancer progression. Although extensive research is done on its toxicity still not much is known about its genotoxic potential on humans in relation to genetic polymorphism. Cytochrome P450 (CYP P-450) and glutathione-S-transferases (GSTs) are important in cellular detoxification of TCE. Variations in gene sequences result in population specific regional genetic variations (polymorphism). Genotyping of CYP1A1, GSTM1, GSTT1 and GSTP1 polymorphism was performed in 220 normal and 97 solvent-exposed individuals from northern part of India using real time PCR, PCR and restriction digestion techniques. The parameters examined to study genotoxicity were chromosomal aberration (CA) and cytokinesis block micronucleus assay (CBMN) in lymphocyte culture in vitro. The observed average frequencies for GSTM1 (null) and GSTT1 (null) were 41, 22 and 12.7%, respectively in normal subjects whereas frequencies of CYP1A1/GSTP1 with (ile/ile) or (ile/val) or(val/val) were found to be 76.2/52, 21.4/42.1 and 2.4/5.9% respectively. It was further observed that the frequencies of above genes were found to be similar in solvent exposed groups. The distribution frequencies of GST genes, when compared with other reports from various regions of India show variations. In vitro TCE exposure (2, 4 and or 6 mM) did not show any significant genotoxic effect. TCE maybe toxic due to its metabolite.
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PMID:Study of genetic polymorphism in solvent exposed population and its correlation to in vitro effect of trichloroethylene on lymphocytes. 2013 49

CYP1A1 and CYP1B1 are two extrahepatic enzymes that have been implicated in carcinogenesis and cancer progression. Selective inhibition of CYP1A1 and CYP1B1 by dietary constituents, notably the class of flavonoids, is a widely accepted paradigm that supports the concept of dietary chemoprevention. In parallel, recent studies have documented the ability of CYP1 enzymes to selectively metabolize dietary flavonoids to conversion products that inhibit cancer cell proliferation. In the present study we have examined the inhibition of CYP1A1 and CYP1B1-catalyzed EROD activity by 14 different flavonoids containing methoxy- and hydroxyl-group substitutions as well as the metabolism of the monomethoxylated CYP1-flavonoid inhibitor acacetin and the poly-methoxylated flavone eupatorin-5-methyl ether by recombinant CYP1A1 and CYP1B1. The most potent inhibitors of CYP1-EROD activity were the methoxylated flavones acacetin, diosmetin, eupatorin and the di-hydroxylated flavone chrysin, indicating that the 4'-OCH(3) group at the B ring and the 5,7-dihydroxy motif at the A ring play a prominent role in EROD inhibition. Potent inhibition of CYP1B1 EROD activity was also obtained for the poly-hydroxylated flavonols quercetin and myricetin. HPLC metabolism of acacetin by CYP1A1 and CYP1B1 revealed the formation of the structurally similar flavone apigenin by demethylation at the 4'-position of the B ring, whereas the flavone eupatorin-5-methyl ether was metabolized to an as yet unidentified metabolite assigned E(5)M1. Eupatorin-5-methyl ether demonstrated a submicromolar IC(50) in the CYP1-expressing cancer cell line MDA-MB 468, while it was considerably inactive in the normal cell line MCF-10A. Homology modeling in conjunction with molecular docking calculations were employed in an effort to rationalize the activity of these flavonoids based on their CYP1-binding mode. Taken together the data suggest that dietary flavonoids exhibit three distinct modes of action with regard to cancer prevention, based on their hydroxyl and methoxy decoration: (1) inhibitors of CYP1 enzymatic activity, (2) CYP1 substrates and (3) substrates and inhibitors of CYP1 enzymes.
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PMID:Comparative CYP1A1 and CYP1B1 substrate and inhibitor profile of dietary flavonoids. 2148 71

Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1, CYP1B1) and other enzymes can activate PAHs to reactive oxygenated intermediates involved in mutagenesis and tumor initiation; also, CYP1 enzymes can detoxify PAHs. Cyp1(+/+) wild-type (WT) and Cyp1b1(-/-) knockout mice receiving oral BaP (12.5 mg/kg/day) remain healthy for >12 months. In contrast, we found that global knockout of the Cyp1a1 gene (1a1KO) results in proximal small intestine (PSI) adenocarcinoma within 8-12 weeks on this BaP regimen; striking compensatory increases in PSI CYP1B1 likely participate in initiation of adenocarcinoma in 1a1KO mice. Cyp1a1/1b1(-/-) double-knockout (DKO) mice on this BaP regimen show no PSI adenocarcinoma, but instead preputial gland duct (PGD) squamous cell carcinoma (SCC) occurs by 12 weeks. Herein, we compare microarray expression of PGD genes in WT, 1a1KO and DKO mice at 0, 4, 8, 12 and 16 weeks of oral BaP; about four dozen genes up- or down-regulated during most critical time-points were further verified by qRT-PCR. In DKO mice, CYP3A59 was unequivocally identified as the BaP-inducible and BaP-metabolizing best candidate responsible for initiation of BaP-induced SCC. Striking increases or decreases were found in 26 cancer-related genes plus eight Serpin genes in DKO, but not in 1a1KO or WT, mice on this BaP regimen; of the 26, 8 were RAS-related oncogenes. The mechanism by which cancer-related genes are responsible for SCC tumor progression in the PGD remains to be elucidated.
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PMID:Oral benzo[a]pyrene in Cyp1a1/1b1(-/-) double-knockout mice: Microarray analysis during squamous cell carcinoma formation in preputial gland duct. 2304 65


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