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  • Books
  • DKFZ Publication Database  (2)
  • PROSTATE-CANCER  (2)
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  • Books
  • DKFZ Publication Database  (2)
  • 1
    Keywords: EXPRESSION ; LINES ; INDUCTION ; PROSTATE-CANCER ; TRANS-RETINOIC ACID ; HUMAN HACAT KERATINOCYTES ; HUMAN NEURO-BLASTOMA ; PROLIFERATOR-ACTIVATED-RECEPTOR ; FENRETINIDE-INDUCED APOPTOSIS ; BETA/DELTA
    Abstract: RETINOIC ACID (RA) HAS PARADOXICAL EFFECTS ON CANCER CELLS: promoting cell death, differentiation and cell cycle arrest, or cell survival and proliferation. Arachidonic acid (AA) release occurs in response to RA treatment and, therefore, AA and its downstream metabolites may be involved in cell survival signalling. To test this, we inhibited phospholipase A2-mediated AA release, cyclooxygenases and lipoxygenases with small-molecule inhibitors to determine if this would sensitise cells to cell death after RA treatment. The data suggest that, in response to RA, phospholipase A2-mediated release of AA and subsequent metabolism by lipoxygenases is important for cell survival. Evidence from gene expression reporter assays and PPARdelta knockdown suggests that lipoxygenase metabolites activate PPARdelta. The involvement of PPARdelta in cell survival is supported by results of experiments with the PPARdelta inhibitor GSK0660 and siRNA-mediated knockdown. Quantitative reverse transcriptase PCR studies demonstrated that inhibition of 5-lipoxygenase after RA treatment resulted in a strong up-regulation of mRNA for PPARdelta2, a putative inhibitory PPARdelta isoform. Over-expression of PPARdelta2 using a tetracycline-inducible system in neuroblastoma cells reduced proliferation and induced cell death. These data provide evidence linking lipoxygenases and PPARdelta in a cell survival-signalling mechanism and suggest new drug-development targets for malignant and hyper-proliferative diseases.
    Type of Publication: Journal article published
    PubMed ID: 23874790
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  • 2
    Keywords: CANCER ; tumor ; MODEL ; NEW-YORK ; RISK ; GENE ; GENES ; TUMORS ; ASSOCIATION ; SUSCEPTIBILITY ; BREAST-CANCER ; genetics ; colorectal cancer ; COLORECTAL-CANCER ; PROSTATE-CANCER ; genotyping ; HIGH-RISK ; REPLICATION ; heredity ; RE ; VARIANT ; SNPs ; METAANALYSIS ; ALLELES ; analysis ; PHASE ; USA ; ENGLAND ; GENOME-WIDE ASSOCIATION ; SCAN ; EIF3S3
    Abstract: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P 〈 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping ( 10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P=2.5 x 10(-13) overall; P=6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P=3.3 x 10(-18) overall; P=9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition
    Type of Publication: Journal article published
    PubMed ID: 18372905
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