The 15-Lipoxygenase-1 Product 13-S-Hydroxyoctadecadienoic Acid Down-Regulates PPAR-δ to Induce Apoptosis in Colorectal Cancer Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 17; pp. 9968 - 9973
• Main Authors: Shureiqi, Imad, Jiang, Wei, Zuo, Xiangsheng, Wu, Yuanqing, Stimmel, Julie B., Leesnitzer, Lisa M., Morris, Jeffrey S., Fan, Hui-Zhen, Fischer, Susan M., Lippman, Scott M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.08.2003; National Acad Sciences
• Subjects: Acids; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Apoptosis; Apoptosis - drug effects; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; Base Sequence; Biological Sciences; Celecoxib; Cell growth; Cell lines; Cells; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Down regulation; Epithelial cells; HCT116 cells; Humans; Linoleic Acids - metabolism; Linoleic Acids - pharmacology; Mice; Mice, Nude; Models, Biological; Neoplasm Transplantation; Protein Binding; Pyrazoles; Receptors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Signal Transduction; Sulfonamides - pharmacology; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1631086100

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-α 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 PPARδ by 15-LOX-1 through 13-S-HODE is an apoptotic signaling pathway that is activated by NSAIDs.