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)

Epidemiologically, a high-fat diet is associated with the risk of colon cancer. In addition, serum levels of triglycerides (TGs) and cholesterol have been demonstrated to be positively associated with colon carcinogenesis. We recently found that an age-dependent hyperlipidemic state (high serum TG levels) exists in Apc-deficient mice, an animal model for human familial adenomatous polyposis. The mRNA levels of lipoprotein lipase (LPL), which catalyzes TG hydrolysis, were shown to be downregulated in the liver and intestines of mice. Moreover, treatment with a peroxisome proliferator-activated receptor (PPAR) alpha agonist, bezafibrate, or a PPARgamma agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in the mice, with induction of LPL mRNA. PPARalpha and PPARgamma agonists are reported to exert anti-proliferative and pro-apoptotic effects in cancer cells. One compound that also increases LPL expression levels but does not possess PPAR agnostic activity is NO-1886. When given at 400 or 800 ppm in the diet, it suppresses both hyperlipidemia and intestinal polyp formation in Apc-deficient mice, with elevation of LPL mRNA. In conclusion, a decrease in serum lipid levels by increasing LPL activity may contribute to a reduction in intestinal polyp formation with Apc deficiency. PPARalpha and PPARgamma agonists, as well as NO-1886, could be useful as chemopreventive agents for colon cancer.
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PMID:Concomitant suppression of hyperlipidemia and intestinal polyp formation by increasing lipoprotein lipase activity in Apc-deficient mice. 1660 35

N-3 polyunsaturated fatty acids (PUFA) and genistein have been associated with lowered cancer risk by reducing inflammatory prostanoids, cyclooxygenase-2 (COX-2) activity, and altering cell signaling. Few studies have investigated the effect of these compounds in combination on the molecular control of the COX-2 gene. In a series of experiments we examined a potential synchronous action of n-3 PUFA and genistein in down-regulating COX-2 expression to diminish prostaglandin E(2) (PGE(2)) production in MDA-MB-231 human breast cancer cells. Cells were treated with genistein and various PUFA including arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PGE(2) concentrations, expression of COX-2, and cell invasiveness were determined. The n-3 PUFA and genistein alone lowered PGE(2) concentration, and genistein in combination with AA reversed the high level of this prostanoid in cell cultures enriched with AA. The degree of cell invasiveness was reversed by genistein in cell cultures treated with AA and further reduced in those given DHA. The n-3 PUFA, in contrast to AA, reduced COX-2 and NFkappaB expression. Genistein combined with AA reversed the effects of AA alone on the expression of COX-2 and NFkappaB. All three fatty acids increased the expression of PPARgamma in the cells only when combined with genistein. Our results support the premise that DHA and genistein exert complementary actions whilst genistein is antagonistic to AA for controlling PGE(2) production as well as invasiveness of MDA-MB-231 cells in culture by modulating the level of NFkappaB expression.
Carcinogenesis 2007 Apr
PMID:Complementary actions of docosahexaenoic acid and genistein on COX-2, PGE2 and invasiveness in MDA-MB-231 breast cancer cells. 1705 99

Cadmium is an environmental toxic metal implicated in human prostate carcinogenesis. The mechanism of its toxicity is not fully understood. Previously, we showed that cadmium exposure induces oxidative stress, especially lipid peroxidation. This study evaluates the effect of chronic exposure to 0.886 mM of cadmium (Cd) per liter in the drinking water on prostate lipid content and metabolism in Wistar rats. We determined the lipid profile and measured the expression of lipogenic enzymes: FAS, GPAT, LPL, DGAT-1, DGAT-2, ACO, CPT-1 and CT, and of certain factors involved in lipid regulation and fatty acid transporters: FAT/CD36, E-FABP, SREBP-2, PPAR-gamma and PPAR-alpha by RT-PCR. Ultrastructure was analyzed by electron microscopy and, as prostate is an androgen controlled gland, AR expression was measured by RT-PCR and Western blot. Cd altered the prostatic lipid profile. Triglycerides (TG) and esterified cholesterol (EC) decreased, free cholesterol (FC) and phospholipids (PL) increased and total cholesterol (TC) did not change. FAS, MDH and IDH activities did not vary but G6PDH decreased significantly in Cd group. Regarding TG synthesis, DGAT-1 decreased while GPAT increased and FAS, LPL and DGAT-2 remained unchanged. Regarding beta oxidation, CPT-1 increased while ACO expression decreased in Cd group. In the PL pathway, CT expression was increased. All these results would justify the decrease of TG in Cd group when compared to control. In the cholesterol metabolic pathway, HMGCoAR and SREBP-2 increased. PPAR-alpha increased but PPAR-gamma did not change. Regarding fatty acid transporters, FAT/CD36 decreased, while E-FABP increased. AR mRNA and protein expression decreased. Ultrastructural analysis showed a decrease in lipid droplets and signs of cellular damage in the Cd group. Cadmium exposure induces important changes in prostatic lipid profile and metabolism, confirmed by the morphology analyses, which also showed signs of cellular damage. These results could be important to further understanding the complex mechanism of cadmium toxicity in prostate and in the development of better treatments for people and animals exposed to the heavy metal.
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PMID:Effects of chronic exposure to cadmium on prostate lipids and morphology. 1706 26

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor family. In colon, this transcription factor is involved in differentiation of absorptive cells. PPARgamma participates also in colon carcinogenesis and cancer progression. Two isoforms, namely PPARgamma1 and PPARgamma2, have been described. Recently, new PPARgamma1 transcripts whose translation raises PPARgamma1 protein have been characterised. They differ from each other by combination of untranslated exons localised in the 5' UTR of the PPARG gene. Here, we studied whether such a diversity of PPARgamma transcripts occurs in human colon cell models. Based on bioinformatic analysis, putative untranslated exons were identified in the human PPARG gene. By RT-PCR analysis, we have demonstrated that several of these untranslated exons are included in PPARgamma transcripts from colon-derived cell lines or in those derived from other tissue. Using HT-29 cells, changes in PPARgamma1 mRNA levels were observed after treatment with PPARgamma agonists such as pioglitazone and troglitazone. These modifications correlated with particular PPARgamma transcripts excluding the untranslated exon A2. HT-29 cells treatment with actinomycin D or cycloheximide showed that the presence of PPARgamma mRNA including exon A2 was dependent on de novo protein synthesis. We concluded that diverse PPARgamma1 mRNA exist in colorectal cells. Levels of PPARgamma1 transcript varied according to the phenotype of colon cell model used. We suggest that regulation of PPARgamma1 mRNA levels could be dependent in part on the composition of untranslated exon(s) in the 5' UTR of PPARgamma1 mRNA.
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PMID:Genetic analysis of peroxisome proliferator-activated receptor gamma1 splice variants in human colorectal cell lines. 1708 2

Fat intake and obesity are positively correlated with pancreatic cancer in humans. N-nitrosobis(2-oxopropyl)amine (BOP) induces pancreatic ductal adenocarcinomas limited to Syrian golden hamsters, other rodents not being susceptible. In the present study, we found markedly high levels of serum triglycerides (TGs) and total cholesterol (TC) in Syrian golden hamsters, but not C57BL/6 mice, ICR mice, F344 rats and Wistar rats. Consistent with this, lipoprotein lipase (LPL) activities in the liver were lower in hamsters compared with mice and rats. To examine effects of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, on LPL expression, serum lipid levels and pancreatic cancer development, 6-week-old female Syrian golden hamsters were subcutaneously injected with BOP (10 mg/kg body wt) four times in a week and thereafter fed a diet containing 800 p.p.m. pioglitazone for 22 weeks. The treatment elevated LPL mRNA expression in the liver and significantly improved hyperlipidemia with serum levels of TG and TC being decreased to 62 and 71%, respectively, of the control values. Concurrently, the incidence and multiplicity of pancreatic ductal adenocarcinomas were significantly decreased by pioglitazone in comparison with the controls (38 versus 80%, P < 0.01 and 0.55 +/- 0.15 versus 1.37 +/- 0.22, P < 0.01, respectively). The suppression rates were greater in invasive adenocarcinomas than non-invasive ones. The incidence of cholangiocellular carcinomas was also reduced. Thus, suppression of pancreatic adenocarcinoma development by pioglitazone is possibly associated with improvement in the serum lipid profile, and hyperlipidemia could be an enhancing factor for development of pancreatic cancer in hamsters.
Carcinogenesis 2007 Aug
PMID:Suppression of N-nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamsters by pioglitazone, a ligand of peroxisome proliferator-activated receptor gamma. 1744 4

FUS-DDIT3 is a chimeric oncogene generated by the most common chromosomal translocation t(12;16)(q13;p11) associated to liposarcomas. The application of transgenic methods and the use of primary mesenchymal progenitor cells to the study of this sarcoma-associated FUS-DDIT3 gene fusion have provided insights into their in vivo functions and suggested mechanisms by which lineage selection may be achieved. These studies indicate that FUS-DDIT3 contributes to differentiation arrest acting at a point in the adipocyte differentiation process after induction of peroxisome proliferator-activated receptor gamma (PPARgamma) expression. To test this idea within a living mouse, we generated mice expressing FUS-DDIT3 within aP2-positive cells, because aP2 is a downstream target of PPARgamma expressed at the immature adipocyte stage. Here, we report that FUS-DDIT3 expression was successfully induced at the aP2 stage of differentiation both in vivo and in vitro. aP2-FUS-DDIT3 mice do not develop liposarcomas and exhibit an increase in white adipose tissue size. Consistent with in vivo data, mouse embryonic fibroblasts (MEFs) obtained from aP2-FUS-DDIT3 mice not only were capable of terminal differentiation but also showed an increased capacity for adipogenesis in vitro compared with wild-type MEFs. Taken together, this study provides genetic evidence that the presence of FUS-DDIT3 in an aP2-positive cell is not enough to cause liposarcoma development and establishes that PPARgamma inactivation is required for liposarcoma development.
Carcinogenesis 2007 Oct
PMID:Fat-specific FUS-DDIT3-transgenic mice establish PPARgamma inactivation is required to liposarcoma development. 1746 15

Human PCAN1 (prostate cancer gene 1) is a prostate-specific gene that is highly expressed in prostate epithelial tissue, and frequently mutated in prostate tumors. To better understand the regulation of the PCAN1 gene, a 2.6-kb fragment of its 5' flanking region was obtained by PCR. Its promoter activity was examined via the dual-luciferase reporter assay after it had been cloned into a pGL(3)-basic vector generating pGL(3)-p2.6 kb and transfected into LNCaP cells. pGL(3)-basic and pGL(3)-control were respectively used as the negative and positive controls. Sequence analysis with the MatInspector database showed that some possible binding sites for the transcriptional factors, NKX3.1, P53, SP1, cEBP and the PPAR/RXR heterodimers may locate on a 2.6-kb region upstream of the PCAN1 gene. To examine the relevant regulation of PCAN1, pGL(3)-p2.6 kb was transfected into the prostate cancer cell line LNCaP, which was treated with R1881 (10(-7) approximately 10(-9) mol/l), 17beta-estradiol (17beta-E(2), 10(-7) approximately 10(-9) mol/l), all-trans-retinoic acid (all-trans-RA, 10(-5) approximately 10(-7) mol/l) or 9-cis-retinoic acid (9-cis-RA, 10(-5) approximately 10(-7) mol/l), and eukaryotic expression plasmids of NKX3.1, p53, Sp1, Pten, PPARgamma or cEBPalpha were cotransfected with pGL(3)-p2.6 kb into LNCaP cells. pRL-TK, a Renilla luciferase reporter vector, was cotransfected into all the transfection lines as an internal control. The activities of pGL(3)-p2.6 kb (PCAN1 promoter) were analyzed via the dual-luciferase reporter assay 48 h after transfection. The results showed that 9-cis-RA enhanced the PCAN1 promoter activity in a dose-dependent manner, while R1881, 17beta-E(2) and all-trans-RA had no significant effect on PCAN1 promoter activities. Cotransfection with pGL(3)-p2.6kb and the expression plasmids of NKX3.1, p53, Sp1 or Pten respectively resulted in 1.66-, 2.48-, 2.00-and 1.72-fold 2.6 kb PCAN1 promoter activity increases relative to the controls, which were cotransfected with pcDNA3.1(+), while cotransfection of PPARgamma and cEBPalpha yielded no significant effect on PCAN1 promoter activities. These results could be applied for further study of the function and transcription regulation of the PCAN1 gene in prostate development and carcinogenesis.
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PMID:Molecular cloning and analysis of the human PCAN1 (GDEP) promoter. 1746 39

Suppression of colon carcinogenesis by peroxisome proliferator-activated receptor (PPAR)-gamma is likely due to some effect of PPAR-gamma on normal colonic epithelial cells. However, our understanding of the effects of PPAR-gamma in such cells is limited. We analyzed the abundance, distribution, and function of PPAR-gamma in epithelial cells isolated from the murine proximal and distal colon. Marked differences in PPAR-gamma abundance and distribution were observed, suggesting tissue-specific responses. Analysis of PPAR-gamma effects on DNA synthesis, formation of preneoplastic lesions, and activation of MAPK signaling in proximal and distal colonic epithelial cells in vivo indicates that PPAR-gamma regulates both tissue-specific and common responses within the proximal and distal colon. Three major functional cohorts of PPAR-gamma target genes were identified by genomic profiling of isolated colonic epithelial cells: genes that are involved in metabolism, in signaling, and in cellular adhesion and motility. Two subsets of PPAR-gamma target genes were differentially expressed in the proximal and distal epithelium. Proximal target genes were primarily involved in metabolic activities, whereas signal transduction, adhesion, and motility targets were more pronounced in the distal colon. Remarkably, those target genes that are differentially expressed in the proximal colon were all induced on activation of PPAR-gamma, whereas all target genes that are preferentially expressed in the distal colon were repressed. Our data indicate that PPAR-gamma exerts both common and tissue-specific effects in the colon and challenge the general conclusions that PPAR-gamma is induced on differentiation of colonic epithelial cells and that this receptor stimulates differentiated function in epithelial cells throughout the colon.
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PMID:Differential expression, distribution, and function of PPAR-gamma in the proximal and distal colon. 1751 61

WNT signals are transduced to the canonical pathway for cell fate determination, and to the noncanonical pathway for control of cell movement and tissue polarity. Canonical WNT signals are transduced through Frizzled family receptors and LRP5/LRP6 coreceptor to the beta-catenin signaling cascade. Microtubule affinity-regulating kinase (PAR-1) family kinases, casein kinase I epsilon (CKI epsilon), and FRAT are positive regulators of the canonical WNT pathway, whereas APC, AXIN1, AXIN2, CKI alpha, NKD1, NKD2, beta TRCP1, beta TRCP2, ANKRD6, Nemo-like kinase (NLK), and peroxisome proliferator-activated receptor gamma (PPAR gamma) are negative regulators. Nuclear complex, consisting of T-cell factor/lymphoid enhancer factor, beta-catenin, BCL9/BCL9L, and PYGO, activates transcription of canonical WNT target genes such as FGF20, DKK1, WISP1, MYC, CCND1, and Glucagon (GCG). Noncanonical WNT signals are transduced through Frizzled family receptors and ROR2/RYK coreceptors to the Dishevelled-dependent (Rho family GTPases and c-jun NH(2)-terminal kinase) or the Ca(2+)-dependent (NLK and nuclear factor of activated T cells) signaling cascades. WNT signals are context-dependently transduced to both pathways based on the expression profile of WNT, SFRP, WIF, DKK, Frizzled receptors, coreceptors, and the activity of intracellular WNT signaling regulators. Epigenetic silencing and loss-of-function mutation of negative regulators of the canonical WNT pathway occur in a variety of human cancer. WNT, fibroblast growth factor (FGF), Notch, Hedgehog, and transforming growth factor beta/bone morphogenetic protein signaling network are implicated in the maintenance of tissue homeostasis by regulating self-renewal of normal stem cells as well as proliferation or differentiation of progenitor (transit-amplifying) cells. Breakage of the stem cell signaling network leads to carcinogenesis. Nonsteroidal anti-inflammatory drugs and PPAR gamma agonists with the potential to inhibit the canonical WNT signaling pathway are candidate agents for chemoprevention. ZTM000990 and PKF118-310 are lead compounds targeted to the canonical WNT signaling cascade. Anti-WNT1 and anti-WNT2 monoclonal antibodies show in vitro effects in cancer treatment. After the optimization, derivatives of small-molecule compound and human monoclonal antibody targeted to the WNT signaling pathway could be used in cancer medicine.
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PMID:WNT signaling pathway and stem cell signaling network. 1763 27

Peroxisome proliferator-activated receptor gamma (PPARgamma) a member of the nuclear transcription factor superfamily is playing a role in colon carcinogenesis. Although not all in vivo models agree, PPARgamma seems to have suppressive effects in this process favoring apoptosis and inhibiting the cell cycle by inducing expression of apoptosis and senescence proteins. With the recent discovery that anti-diabetic class of drugs thiazolidinediones act through activation of PPARgamma, interest in this transcription factor has increased as it can now be pharmacologically activated in order to obtain tumor suppression. In addition, thiazolidinediones and other PPARgamma agonists possess PPARgamma-independent anti-tumor effects. Although PPARgamma agonists may not by themselves be capable to induce clinical tumor regression, their combination with chemotherapy drugs or other targeted therapies is worth pursuing in the treatment of colorectal carcinoma.
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PMID:Peroxisome proliferator-activated receptor gamma (PPARgamma) and colorectal carcinogenesis. 1765 59


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