Abstract
Diminished apoptosis, a critical event in tumorigenesis, is linked to down-regulated 15-lipoxygenase-1 (15-LOX-1) expression in colorectal cancer cells. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which is the primary product of 15-LOX-1 metabolism of linoleic acid, restores apoptosis. Nonsteroidal antiinflammatory drugs (NSAIDS) transcriptionally up-regulate 15-LOX-1 expression to induce apoptosis. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for linoleic and arachidonic acid metabolites. PPAR-δ promotes colonic tumorigenesis. NSAIDs suppress PPAR-δ activity in colon cancer cells. The mechanistic relationship between 15-LOX-1 and PPAR-δ was previously unknown. Our current study shows that (i) 13-S-HODE binds to PPAR-δ, decreases PPAR-δ activation, and down-regulates PPAR-δ expression in colorectal cancer cells (ii) the induction of 15-LOX-1 expression is a critical step in NSAID down-regulation of PPAR-δ and the resultant induction of apoptosis; and (iii) PPAR-δ is an important signaling receptor for 13-S-HODE-induced apoptosis. The in vivo relevance of these mechanistic findings was demonstrated in our tumorigenesis studies in nude mouse xenograft models. Our findings indicate that the down-regulation of PPAR-δ by 15-LOX-1 through 13-S-HODE is an apoptotic signaling pathway that is activated by NSAIDs.
Original language | English (US) |
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Pages (from-to) | 9968-9973 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 100 |
Issue number | 17 |
DOIs | |
State | Published - Aug 19 2003 |
ASJC Scopus subject areas
- General