The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-δ 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-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.

[1]  B. Levin,et al.  The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. , 2000, The New England journal of medicine.

[2]  S. Blanchard,et al.  Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain. , 1998, Analytical biochemistry.

[3]  W. Bodmer,et al.  Failure of programmed cell death and differentiation as causes of tumors: some simple mathematical models. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  K. Umesono,et al.  Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors , 1992, Nature.

[5]  B. Rigas,et al.  Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells. , 1995, The Journal of clinical investigation.

[6]  J. Ward,et al.  Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ) , 2000, Molecular and Cellular Biology.

[7]  P. Hall,et al.  Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. , 1994, Journal of cell science.

[8]  T. Willson,et al.  Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  S. Lippman,et al.  GATA-6 transcriptional regulation of 15-lipoxygenase-1 during NSAID-induced apoptosis in colorectal cancer cells. , 2002, Cancer research.

[10]  S. Piantadosi,et al.  Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. , 1993, The New England journal of medicine.

[11]  V. Steele,et al.  Modulation of apoptosis by sulindac, curcumin, phenylethyl-3-methylcaffeate, and 6-phenylhexyl isothiocyanate: apoptotic index as a biomarker in colon cancer chemoprevention and promotion. , 1997, Cancer research.

[12]  Bert Vogelstein,et al.  Genetic disruption of PPARδ decreases the tumorigenicity of human colon cancer cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  S. Lippman,et al.  15-Lipoxygenase-1 mediates nonsteroidal anti-inflammatory drug-induced apoptosis independently of cyclooxygenase-2 in colon cancer cells. , 2000, Cancer research.

[14]  K. Kinzler,et al.  PPARδ Is an APC-Regulated Target of Nonsteroidal Anti-Inflammatory Drugs , 1999, Cell.

[15]  I. Shureiqi,et al.  Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers. , 1999, Carcinogenesis.

[16]  D. Alberts,et al.  Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. , 1995, Cancer research.

[17]  S. Lippman,et al.  15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells. , 2000, Journal of the National Cancer Institute.

[18]  J. Lehmann,et al.  Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. , 2000, Molecular cell.

[19]  D. Nicholson,et al.  From bench to clinic with apoptosis-based therapeutic agents , 2000, Nature.

[20]  Scott W. Lowe,et al.  Apoptosis A Link between Cancer Genetics and Chemotherapy , 2002, Cell.

[21]  A. Brash,et al.  Discovery of a second 15S-lipoxygenase in humans. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Evans,et al.  Nuclear receptors and lipid physiology: opening the X-files. , 2001, Science.

[23]  G. Evan,et al.  Proliferation, cell cycle and apoptosis in cancer , 2001, Nature.