The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells.
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-delta promotes colonic tumorigenesis. NSAIDs suppress PPAR-delta activity in colon cancer cells. The mechanistic relationship between 15-LOX-1 and PPAR-delta was previously unknown. Our current study shows that (i) 13-S-HODE binds to PPAR-delta, decreases PPAR-delta activation, and down-regulates PPAR-delta expression in colorectal cancer cells; (ii) the induction of 15-LOX-1 expression is a critical step in NSAID down-regulation of PPAR-delta and the resultant induction of apoptosis; and (iii) PPAR-delta 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-delta by 15-LOX-1 through 13-S-HODE is an apoptotic signaling pathway that is activated by NSAIDs.
Shureiqi
Imad
I
Departments of Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. ishureiqi@mdanderson.org
Jiang
Wei
W
Zuo
Xiangsheng
X
Wu
Yuanqing
Y
Stimmel
Julie B
JB
Leesnitzer
Lisa M
LM
Morris
Jeffrey S
JS
Fan
Hui-Zhen
HZ
Fischer
Susan M
SM
Lippman
Scott M
SM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D006801:Humans; D008041:Linoleic Acids / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D011485:Protein Binding; D011720:Pyrazoles; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008041:Linoleic Acids; D011720:Pyrazoles; D012334:RNA, Neoplasm; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014157:Transcription Factors; C024348:13-hydroxy-9,11-octadecadienoic acid; D001093:Arachidonate 15-Lipoxygenase; D000068579:Celecoxib