Peroxisome-proliferator-activated receptors γ and β/δ mediate vascular endothelial growth factor production in colorectal tumor cells

AbstractBackgroundPeroxisome-proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids and their derivatives. PPAR subtypes PPARγ and PPARβ/δ are suspected to modulate cancer development in the colon, but their exact role is still discussed controversially.MethodsThe present study investigated the impact of PPARγ and PPARβ/δ on vascular endothelial growth factor (VEGF) and cyclooxygenase 2 (COX-2) expressions induced by synthetic and physiological agonists in the colorectal tumor cell lines SW480 and HT29 using reporter gene assays, qRT-PCR and ELISA.ResultsActivation of both PPARγ and PPARβ/δ induced expression of VEGF mRNA and protein in a PPAR-dependent way. The PPARγ agonists ciglitazone and PGJ2 were the most effective inducers with up to ninefold and threefold increases in VEGF mRNA in SW480 and HT29 cultures, respectively. VEGF secretion was doubled in both cell lines. The PPARβ/δ agonists GW501516 and PGI2 caused stimulations of only 1.5-fold in both cell lines. In addition, all PPAR agonists induced COX-2 mRNA and secretion of the COX-2 product PGE2 in HT29 cells. However, this effect was not blocked by knock-down of PPAR expression nor was it essential for VEGF expression as shown by the lack of effect of the COX-2 inhibitor SC236.Conclusion In summary, our results identify both PPARγ and PPARβ/δ as an alternative COX-independent mechanism of VEGF induction in colorectal tumor cells.

[1]  D. Schwartz,et al.  Role of beta-catenin/T-cell factor-regulated genes in ovarian endometrioid adenocarcinomas. , 2002, The American journal of pathology.

[2]  K. Kinzler,et al.  Genetic disruption of PPARdelta decreases the tumorigenicity of human colon cancer cells. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Orfeo,et al.  One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. , 1977, Journal of the National Cancer Institute.

[4]  W. Carney,et al.  Detection of p21ras mutations in colorectal adenomas and carcinomas by enzyme‐linked immunosorbent assay , 1995, Cancer.

[5]  B. Marian,et al.  Bile acid induced gene expression in LT97 colonic adenoma cells. , 2005, Food and Chemical Toxicology.

[6]  J. Roman,et al.  Activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) increases the expression of prostaglandin E2 receptor subtype EP4. The roles of phosphatidylinositol 3-kinase and CCAAT/enhancer-binding protein beta. , 2005, The Journal of biological chemistry.

[7]  Lihong Xu,et al.  A Novel Positive Feedback Loop between Peroxisome Proliferator-activated Receptor-δ and Prostaglandin E2 Signaling Pathways for Human Cholangiocarcinoma Cell Growth* , 2006, Journal of Biological Chemistry.

[8]  Rajnish A. Gupta,et al.  Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2 , 2001, Nature Reviews Cancer.

[9]  R. DuBois,et al.  Peroxisome Proliferator-Activated Receptors and Progression of Colorectal Cancer , 2008, PPAR research.

[10]  B. Evers,et al.  Selective activation of PPARγ inhibits pancreatic cancer invasion and decreases expression of tissue plasminogen activator , 2003 .

[11]  T. Willson,et al.  PPARbeta/delta protects against experimental colitis through a ligand-independent mechanism. , 2007, Digestive diseases and sciences.

[12]  F. Ondrey,et al.  Peroxisome Proliferator-Activated Receptor γ Pathway Targeting in Carcinogenesis: Implications for Chemoprevention , 2009, Clinical Cancer Research.

[13]  Y. Matsuzawa,et al.  Peroxisome Proliferator‐activated Receptor γ Induces Growth Arrest and Differentiation Markers of Human Colon Cancer Cells , 1999, Japanese journal of cancer research : Gann.

[14]  Jeffrey S. Morris,et al.  The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-δ to induce apoptosis in colorectal cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Y. Fujiwara,et al.  PPAR-gamma ligands inhibit growth of human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity. , 2001, International journal of oncology.

[16]  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.

[17]  W. Wahli,et al.  Crosstalk between peroxisome proliferator-activated receptor δ and VEGF stimulates cancer progression , 2006, Proceedings of the National Academy of Sciences.

[18]  A. Mahfoudi,et al.  Functional interactions of peroxisome proliferator-activated receptor, retinoid-X receptor, and Sp1 in the transcriptional regulation of the acyl-coenzyme-A oxidase promoter. , 1995, Molecular endocrinology.

[19]  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.

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

[21]  G. Fürstenberger,et al.  Growth inhibition and induction of apoptosis in colorectal tumor cells by cyclooxygenase inhibitors. , 2001, Carcinogenesis.

[22]  L. Moore,et al.  Subtype specific effects of peroxisome proliferator-activated receptor ligands on corepressor affinity. , 2003, Biochemistry.

[23]  H. Nakagama,et al.  Peroxisome proliferator-activated receptor gamma ligands suppress colon carcinogenesis induced by azoxymethane in mice. , 2003, Gastroenterology.

[24]  W. Wahli,et al.  Multiple expression control mechanisms of peroxisome proliferator-activated receptors and their target genes , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[25]  J. Ward,et al.  Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. , 2004, Nature medicine.

[26]  J. Roman,et al.  Activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) increases the expression of prostaglandin E2 receptor subtype EP4. THE ROLES OF PHOSPHATIDYLINOSITOL 3-KINASE AND CCAAT/ENHANCER-BINDING PROTEIN β. , 2005, The Journal of Biological Chemistry.

[27]  L. Yang,et al.  RNA Interference Against Peroxisome Proliferator-Activated Receptor δ Gene Promotes Proliferation of Human Colorectal Cancer Cells , 2008, Diseases of the colon and rectum.

[28]  A. Hamsten,et al.  PPARδ activation induces COX-2 gene expression and cell proliferation in human hepatocellular carcinoma cells , 2003 .

[29]  T. Willson,et al.  PPARβ/δ Protects Against Experimental Colitis Through a Ligand-Independent Mechanism , 2007, Digestive Diseases and Sciences.

[30]  B. Spiegelman,et al.  Loss-of-function mutations in PPAR gamma associated with human colon cancer. , 1999, Molecular cell.

[31]  T. Willson,et al.  Peroxisome proliferator activated receptor agonists. , 1997, EXS.

[32]  B. Spiegelman,et al.  Loss-of-Function Mutations in PPARγ Associated with Human Colon Cancer , 1999 .

[33]  K. Lim,et al.  Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)alpha/cyclooxygenase-2/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells. , 2006, Cancer research.

[34]  D. Hum,et al.  Safety issues and prospects for future generations of PPAR modulators. , 2007, Biochimica et biophysica acta.

[35]  A. Hamsten,et al.  PPARdelta activation induces COX-2 gene expression and cell proliferation in human hepatocellular carcinoma cells. , 2003, Biochemical and biophysical research communications.

[36]  M. Monden,et al.  Expression of PPARδ in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology , 2006, British Journal of Cancer.

[37]  W. Wahli,et al.  Potential role for peroxisome proliferator activated receptor (PPAR) in preventing colon cancer , 2003, Gut.

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

[39]  Y. Matsuzawa,et al.  PPARgamma agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells. , 2001, International journal of cancer.

[40]  K. Lim,et al.  Cross-talk between Peroxisome Proliferator-Activated Receptor δ and Cytosolic Phospholipase A2α/Cyclooxygenase-2/Prostaglandin E2 Signaling Pathways in Human Hepatocellular Carcinoma Cells , 2006 .

[41]  K. Kristiansen,et al.  Increased levels of PPARbeta/delta and cyclin D1 in flat dysplastic ACF and adenomas in Apc(Min/+) mice. , 2005, Anticancer research.

[42]  Y. Surh,et al.  The role of 15-deoxy-delta(12,14)-prostaglandin J(2), an endogenous ligand of peroxisome proliferator-activated receptor gamma, in tumor angiogenesis. , 2008, Biochemical pharmacology.

[43]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[44]  Rajnish A. Gupta,et al.  Activation of nuclear hormone receptor peroxisome proliferator–activated receptor-δ accelerates intestinal adenoma growth , 2004, Nature Medicine.

[45]  R. Kucherlapati,et al.  Peroxisome proliferator‐activated receptor γ agonist troglitazone induces colon tumors in normal C57BL/6J mice and enhances colonic carcinogenesis in Apc1638 N/+ Mlh1+/− double mutant mice , 2005, International journal of cancer.

[46]  Y. Matsuzawa,et al.  PPARγ agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF‐like growth factors in ras‐transformed rat intestinal epithelial cells , 2001 .

[47]  T. Willson,et al.  Ligand activation of peroxisome proliferator-activated receptor beta inhibits colon carcinogenesis. , 2006, Cancer research.

[48]  N. Ferrara,et al.  The biology of VEGF and its receptors , 2003, Nature Medicine.

[49]  J. Ward,et al.  Peroxisome proliferator–activated receptor-δ attenuates colon carcinogenesis , 2004, Nature Medicine.

[50]  J. Peters,et al.  Role of peroxisome-proliferator-activated receptor beta/delta (PPARbeta/delta) in gastrointestinal tract function and disease. , 2008, Clinical science.

[51]  W. Wahli,et al.  Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. , 1997, Molecular endocrinology.

[52]  W. Wahli,et al.  Differential Regulation of Vascular Endothelial Growth Factor Expression by Peroxisome Proliferator-activated Receptors in Bladder Cancer Cells* , 2002, The Journal of Biological Chemistry.

[53]  T. Muto,et al.  The evolution of cancer of the colon and rectum , 1974, Cancer.

[54]  A. Leibovitz,et al.  Classification of human colorectal adenocarcinoma cell lines. , 1976, Cancer research.

[55]  G. Conn,et al.  Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Béatrice Desvergne,et al.  Peroxisome-proliferator-activated receptors and cancers: complex stories , 2004, Nature Reviews Cancer.

[57]  R. Schulte‐Hermann,et al.  Dietary lipid hydroperoxides induce expression of vascular endothelial growth factor (VEGF) in human colorectal tumor cells , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  W. Wahli,et al.  Peroxisome proliferator-activated receptors: three isotypes for a multitude of functions. , 1999, Current opinion in biotechnology.