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12/15 lipoxygenase regulation of colorectal tumorigenesis is determined by the relative tumor levels of its metabolite 12-HETE and 13-HODE in animal models
- Source :
- Oncotarget
- Publication Year :
- 2014
- Publisher :
- Impact Journals, LLC, 2014.
-
Abstract
- Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. The arachidonic acid (AA) pathway and linoleic acid (LA) pathway have been implicated as important contributors to CRC development and growth. Human 15-lipoxygenase 1 (15-LOX-1) converts LA to anti-tumor 13-S-hydroxyoctadecadienoic acid (13-HODE)and 15-LOX-2 converts AA to 15-hydroxyeicosatetraenoic acid (15-HETE). In addition, human 12-LOX metabolizes AA to pro-tumor 12-HETE. In rodents, the function of 12-LOX and 15-LOX-1 and 15-LOX-2 is carried out by a single enzyme, 12/15-LOX. As a result, conflicting conclusions concerning the role of 12-LOX and 15-LOX have been obtained in animal studies. In the present studies, we determined that PD146176, a selective 15-LOX-1 inhibitor, markedly suppressed 13-HODE generation in human colon cancer HCA-7 cells and HCA-7 tumors, in association with increased tumor growth. In contrast, PD146176 treatment led to decreases in 12-HETE generation in mouse colon cancer MC38 cells and MC38 tumors, in association with tumor inhibition. Surprisingly, deletion of host 12/15-LOX alone led to increased MC38 tumor growth, in association with decreased tumor 13-HODE levels, possibly due to inhibition of 12/15-LOX activity in stroma. Therefore, the effect of 12/15-LOX on colorectal tumorigenesis in mouse models could be affected by tumor cell type (human or mouse), relative 12/15 LOX activity in tumor cells and stroma as well as the relative tumor 13-HODE and 12-HETE levels.
- Subjects :
- Male
linoleic acid
mice
endocrine system diseases
Colorectal cancer
Linoleic acid
Mice, Nude
Tumor M2-PK
Biology
Arachidonate 12-Lipoxygenase
Gene Expression Regulation, Enzymologic
chemistry.chemical_compound
Species Specificity
Stroma
Cell Line, Tumor
arachidonic acid
stroma
medicine
Animals
Arachidonate 15-Lipoxygenase
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
Lipoxygenase Inhibitors
metabolites
Cell Proliferation
Mice, Knockout
integumentary system
Cell growth
Macrophages
epithelial cell
food and beverages
Cancer
medicine.disease
Tumor Burden
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
Linoleic Acids
Oncology
Biochemistry
chemistry
Cell culture
Cancer research
lipids (amino acids, peptides, and proteins)
Arachidonic acid
Colorectal Neoplasms
Signal Transduction
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....613b5fc08cb19e363c4b35b3524d9954