Genetic disruption of PPARδ decreases the tumorigenicity of human colon cancer cells

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that have been implicated in a variety of biologic processes. The PPARδ isotype was recently proposed as a downstream target of the adenomatous polyposis coli (APC)/β-catenin pathway in colorectal carcinogenesis. To evaluate its role in tumorigenesis, a PPARδ null cell line was created by targeted homologous recombination. When inoculated as xenografts in nude mice, PPARδ −/− cells exhibited a decreased ability to form tumors compared with PPARδ +/− and wild-type controls. These data suggest that suppression of PPARδ expression contributes to the growth-inhibitory effects of the APC tumor suppressor.

[1]  J. G. Alvarez,et al.  Activators of the nuclear receptor PPARγ enhance colon polyp formation , 1998, Nature Medicine.

[2]  M. Miyaki,et al.  Frequent activation of the β‐catenin‐Tcf signaling pathway in nonfamilial colorectal carcinomas with microsatellite instability , 2001, Genes, chromosomes & cancer.

[3]  Bert Vogelstein,et al.  Mutational Analysis of the APC/β-Catenin/Tcf Pathway in Colorectal Cancer , 1998 .

[4]  Frank McCormick,et al.  β-Catenin regulates expression of cyclin D1 in colon carcinoma cells , 1999, Nature.

[5]  Hans Clevers,et al.  Activation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APC , 1997, Science.

[6]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[7]  Barry M. Forman,et al.  Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ , 1997 .

[8]  Y. Doki,et al.  Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  Sander Kersten,et al.  Roles of PPARs in health and disease , 2000, Nature.

[10]  P. Polakis,et al.  Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Kai Yu,et al.  Differential Activation of Peroxisome Proliferator-activated Receptors by Eicosanoids (*) , 1995, The Journal of Biological Chemistry.

[12]  Samuel Singer,et al.  Differentiation and reversal of malignant changes in colon cancer through PPARγ , 1998, Nature Medicine.

[13]  B. Sauer.  Manipulation of transgenes by site-specific recombination: use of Cre recombinase. , 1993, Methods in enzymology.

[14]  S. Shirasawa,et al.  Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. , 1993, Science.

[15]  K. Kinzler,et al.  Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC−/− Colon Carcinoma , 1997, Science.

[16]  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.

[17]  Satoshi Tanaka,et al.  PPARγ Mediates High-Fat Diet–Induced Adipocyte Hypertrophy and Insulin Resistance , 1999 .

[18]  J. Morrow,et al.  Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. , 1999, Genes & development.

[19]  Y. Yamauchi,et al.  Improved dicistronic mRNA expression vectors for efficient selection of transfectants highly expressing foreign genes. , 1996, BioTechniques.

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

[21]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[22]  J. Auwerx,et al.  Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice , 1998, Nature Medicine.

[23]  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.

[24]  K. Kinzler,et al.  Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  K. Kinzler,et al.  14-3-3σ is required to prevent mitotic catastrophe after DNA damage , 1999, Nature.

[26]  W. Wahli,et al.  Peroxisome proliferator-activated receptors: insight into multiple cellular functions. , 2000, Mutation research.