Kim, JS, Baek, SJ, Bottone, FG Jr., Sali, T and Eling, TE. Overexpression of 15-lipoxygenase-1 induces growth arrest through phosphorylation of p53 in human colorectal cancer cells. Mol Cancer Res 3: 511-517

The University of Tennessee Medical Center at Knoxville, Knoxville, Tennessee, United States
Molecular Cancer Research (Impact Factor: 4.38). 10/2005; 3(9):511-7. DOI: 10.1158/1541-7786.MCR-05-0011
Source: PubMed


To investigate the function of 15-lipoxygenase-1 (15-LOX-1) in human colorectal cancer, we overexpressed 15-LOX-1 in HCT-116 human colorectal cancer cells. Clones expressing the highest levels of 15-LOX-1 displayed reduced viability compared with the HCT-116-Vector control cells. Further, by cell cycle gene array analyses, the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and MDM2 genes were up-regulated in 15-LOX-1-overexpressing cells. The induction of p21(WAF1/CIP1) and MDM2 were linked to activation of p53 by 15-LOX-1, as there was a dramatic induction of phosphorylated p53 (Ser15) in 15-LOX-1-overesxpressing cells. However, the 15-LOX-1 metabolites 13(S)-hydroxyoctadecadienoic acid and 15(S)-hydroxyeicosatetraenoic acid failed to induce phosphorylation of p53 at Ser15, and the 15-LOX-1 inhibitor PD146176 did not inhibit the phosphorylation of p53 at Ser15 in 15-LOX-1-overexpressing cells. Nonetheless, the growth-inhibitory effects of 15-LOX-1 were p53 dependent, as 15-LOX-1 overexpression had no effect on cell growth in p53 (-/-) HCT-116 cells. Finally, treatment of HCT-116-15-LOX-1 cells with different kinase inhibitors suggested that the effects of 15-LOX-1 on p53 phosphorylation and activation were due to effects on DNA-dependent protein kinase. Collectively, these findings suggest a new mechanism to explain the biological activity of 15-LOX-1, where 15-LOX plays a stoichiometric role in activating a DNA-dependent protein kinase-dependent pathway that leads to p53-dependent growth arrest.

Download full-text


Available from: Frank Bottone Jr, Jun 06, 2014
  • Source
    • "An example of evidence sentences is ‘Overexpression of 15-lipoxygenase-1 induces growth arrest through phosphorylation of p53 in human colorectal cancer cells.’ from an article (16) explaining a mechanism how phosphorylation of TP53 induced by overexpression of 15-LOX-1 affects growth arrest. In the example (iii), DigSee system returns a list of 394 genes with evidence sentences in which localization and transcription events of these genes are related to brain cancer. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Biological events such as gene expression, regulation, phosphorylation, localization and protein catabolism play important roles in the development of diseases. Understanding the association between diseases and genes can be enhanced with the identification of involved biological events in this association. Although biological knowledge has been accumulated in several databases and can be accessed through the Web, there is no specialized Web tool yet allowing for a query into the relationship among diseases, genes and biological events. For this task, we developed DigSee to search MEDLINE abstracts for evidence sentences describing that 'genes' are involved in the development of 'cancer' through 'biological events'. DigSee is available through
    Nucleic Acids Research 06/2013; 41(Web Server issue). DOI:10.1093/nar/gkt531 · 9.11 Impact Factor
  • Source
    • "In addition, overexpression of the human ortholog 15-LOX-1 induces extracellular signal–related kinase 1/2 phosphorylation, decreased p21 (cip/WAF1) expression, and increased colon cancer growth [18]. Conversely, Kim et al. [19] described an antiproliferative effect of 15-LOX-1 in colorectal cancer cells associated with p53 phosphorylation. In line with these results, Shureiqi et al. reported that 13-HODE induces apoptosis and cell cycle arrest in colorectal cancer cells [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The selenoenzyme glutathione peroxidase 4 (GPx4) has been described to control specific cyclooxygenases (COXs) and lipoxygenases (LOXs) that exert substantiated functions in tumor growth and angiogenesis. Therefore, we hypothesized a putative regulatory role of GPx4 during tumor progression and created transformed murine embryonic fibroblasts with inducible disruption of GPx4. GPx4 inactivation caused rapid cell death in vitro, which could be prevented either by lipophilic antioxidants or by 12/15-LOX-specific inhibitors, but not by inhibitors targeting other LOX isoforms or COX. Surprisingly, transformed GPx4(+/-) cells did not die when grown in Matrigel but gave rise to tumor spheroids. Subcutaneous implantation of tumor cells into mice resulted in knockout tumors that were indistinguishable in volume and mass in comparison to wild-type tumors. However, further analysis revealed a strong vascular phenotype. We observed an increase in microvessel density as well as a reduction in the number of large diameter vessels covered by smooth muscle cells. This phenotype could be linked to increased 12/15-LOX activity that was accompanied by an up-regulation of basic fibroblast growth factor and down-regulation of vascular endothelial growth factor A protein expression. Indeed, pharmacological inhibition of 12/15-LOX successfully reversed the tumor phenotype and led to "normalized" vessel morphology. Thus, we conclude that GPx4, through controlling 12/15-LOX activity, is an important regulator of tumor angiogenesis as well as vessel maturation.
    Neoplasia (New York, N.Y.) 03/2010; 12(3):254-63. DOI:10.1593/neo.91782 · 4.25 Impact Factor
  • Source

Show more