15‐Lipoxygenase‐1 activates tumor suppressor p53 independent of enzymatic activity

Zhu, Hong; Glasgow, Wayne C.; George, Michael H.; Chrysovergis, Kaliopi; Olden, Kenneth; Roberts, John D.; Eling, Thomas E.

doi:10.1002/ijc.23855

Cited by 17 publications

(14 citation statements)

References 40 publications

(48 reference statements)

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“…It has also been demonstrated that the downstream metabolic products of arachidonic and linoleic acid of the 15-LOX-1 pathway (15-S-HETE and 13-S-HODE, respectively) were incapable of inducing this phosphorylation of p53 themselves, which proves that some anti-tumorigenic properties of 15-LOX-1 may be independent of its fatty acid metabolites. The report from Zhu et al [68] has also demonstrated nuclear co-localisation of 15-LOX-1 and DNA-PK, which strengthens the above view.…”

Section: P53-dependent Mechanismsupporting

confidence: 72%

“…Several protein kinases such as MAPK [66] and DNA-dependent protein kinase (DNA-PK) [65] cause phosphorylation of p53 at Ser 15 position. Reports from in vitro studies performed by Kim et al [67] and those by Zhu et al [68] showed that 15-LOX-1 could directly phosphorylate p53 by activating the serine-threonine kinase, DNA-PK, and thus induce apoptosis by decreasing the degradation of p53. It has also been demonstrated that the downstream metabolic products of arachidonic and linoleic acid of the 15-LOX-1 pathway (15-S-HETE and 13-S-HODE, respectively) were incapable of inducing this phosphorylation of p53 themselves, which proves that some anti-tumorigenic properties of 15-LOX-1 may be independent of its fatty acid metabolites.…”

Section: P53-dependent Mechanismmentioning

confidence: 99%

See 1 more Smart Citation

15-Lipoxygenase-1 in Colorectal Cancer: A Review

Bhattacharya¹,

Mathew²,

Jayne³

et al. 2009

Tumor Biol

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Objective: Enzymes involved in the oxidative metabolism of n-6 polyunsaturated fatty acids, like lipoxygenase (LOX) and cyclooxygenase (COX), are significant in the pathogenesis of colorectal cancer. Of these enzymes, 15-LOX-1 is expressed in colon. Aim of this article is to describe the role and regulation of 15-LOX-1 in colorectal cancer and highlight its importance in cancer therapeutics. Methods: For our electronic literature research in PubMed and MEDLINE, key words related to 15-LOX-1 and colorectal cancer were used to find articles for this review. Results: From the evidences, we believe that 15-LOX-1 has anti-carcinogenic effects in colorectal cancer, dependent or independent of its metabolites, and is manifested through downstream pathways involving cGMP, PPAR, p53, p21 and NAG-1, increasing apoptosis and decreasing proliferation in cancer cells. Regulation of 15-LOX-1 expression is achieved at transcription level by global histone acetylation and may also be dependent on GATA-6, IL-4 and IL-13. Positive relationship exists between 15-LOX-1 and survival in colorectal cancer. Conclusion: Evidences strongly support that therapeutic modulation of 15-LOX-1 may be a key to the treatment of colorectal cancer. However, it is still undecided whether the up-regulation of 15-LOX-1 alone can be sufficient to treat colorectal cancer and further studies are awaited.

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Section: P53-dependent Mechanismsupporting

confidence: 72%

Section: P53-dependent Mechanismmentioning

confidence: 99%

15-Lipoxygenase-1 in Colorectal Cancer: A Review

Bhattacharya¹,

Mathew²,

Jayne³

et al. 2009

Tumor Biol

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“…Although 15LO1 was originally identified as a fatty acid metabolic enzyme, it has also been reported to bind to other molecules including phospholipids (24) and proteins (44). In the setting of asthma/Th2 stimulation where 15LO1 protein and its product 15HETE/HETE-PE are highly expressed, its interactions with PEBP1-Raf-1 could dramatically impact ERK activation.…”

Section: Discussionmentioning

confidence: 99%

15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells

Zhao

O'Donnell

Balzar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

119

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Epithelial 15-lipoxygenase 1 (15LO1) and activated ERK are increased in asthma despite modest elevations in IL-13. MAPK kinase (MEK)/ERK activation is regulated by interactions of Raf-1 with phosphatidylethanolamine-binding protein 1 (PEBP1). Epithelial 15LO1 generates intracellular 15-hydroxyeicosatetraenoic acid (15HETE) conjugated to phosphatidylethanolamine (PE) (15HETE-PE). We hypothesized that (i) 15LO1 and its product 15HETE-PE serve as signaling molecules interacting with PEBP1 to activate Raf-1/MEK/ERK and that (ii) this 15LO1-15HETE-PE-regulated ERK activation amplifies IL-4Rα downstream pathways. Our results demonstrate that high epithelial 15LO1 levels correlate with ERK phosphorylation ex vivo. In vitro, IL-13 induces 15LO1, which preferentially binds to PEBP1, causing PEBP1 to dissociate from Raf-1 and activate ERK. Exogenous 15HETE-PE similarly induces dissociation of PEBP1 from Raf-1 independently of IL-13/15LO1. siRNA knockdown of 15LO1 decreases the dissociation of Raf-1 from PEBP1, and the resulting lower ERK activation leads to lower downstream IL-4Rα-related gene expression. Identical proteinprotein interactions are observed in endobronchial biopsies and fresh epithelial cells from asthmatics ex vivo. Colocalization of Raf-1 to PEBP1 is low in asthmatic tissue and cells compared with normals, whereas there is striking colocalization of 15LO1 with PEBP1 in asthma. Low 15LO1 levels in normals limit its colocalization with PEBP1. The results confirm a previously unknown signaling role for 15LO1 and its PE-conjugated eicosanoid product in human airway epithelial cells. This pathway enhances critical inflammatory pathways integral to asthma pathogenesis.

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“…A mutant 15-LOX-1 devoid of enzymatic activity was created by replacing a key histidine with a leucine. Both the mutant and the wild-type protein increased p53 activation, suggesting that activation was independent of enzymatic activity [34]. 15-LOX-1 and DNA-PK co-immunoprecipitated and the kinase activity of the DNA-PK immunoprecipitates was three to four times higher in the presence of 15-LOX-1, supporting the hypothesis that 15-LOX-1 directly increases its kinase activity [34].…”

Section: 15-lipoxygenase and Cancermentioning

confidence: 88%

COX inhibitors directly alter gene expression: role in cancer prevention?

Wang

Baek

Eling

2011

Cancer Metastasis Rev

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Inflammation is an important contributor to the development and progression of human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs) bind to specific receptors that activate signaling pathways driving the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs) are well documented as agents that inhibit tumor growth and with long-term use prevent tumor development. NSAIDs also alter gene expression independent of COX inhibition and these changes in gene expression also appear to contribute to the anti-tumorigenic activity of these drugs. Many NSAIDs, as illustrated by sulindac sulfide, alter gene expressions by altering the expression or phosphorylation status of the transcription factors specificity protein 1 and early growth response-1 with the balance between these two events resulting in increases or decreases in specific target genes. In this review, we have summarized and discussed the various genes altered by this mechanism after NSAID treatment and how these changes in expression relate to the anti-tumorigenic activity. A major focus of the review is on NSAID-activated gene (NAG-1) or growth differentiation factor 15. This unique member of the TGF-β superfamily is highly induced by NSAIDs and numerous drugs and chemicals with anti-tumorigenic activities. Investigations with a transgenic mouse expressing the human NAG-1 suggest it acts to suppress tumor development in several mouse models of cancer. The biochemistry and biology of NAG-1 were discussed as potential contributor to cancer prevention by COX inhibitors.

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15‐Lipoxygenase‐1 activates tumor suppressor p53 independent of enzymatic activity

Cited by 17 publications

References 40 publications

15-Lipoxygenase-1 in Colorectal Cancer: A Review

15-Lipoxygenase-1 in Colorectal Cancer: A Review

15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells

COX inhibitors directly alter gene expression: role in cancer prevention?

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