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


METHODS
The 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.


RESULTS
Activation of both PPARγ and PPARβ/δ induced expression of VEGF mRNA and protein in a PPAR-dependent way. The PPARγ agonists ciglitazone and PGJ(2) 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 PGI(2) 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 PGE(2) 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.


CONCLUSIONS
In summary, our results identify both PPARγ and PPARβ/δ as an alternative COX-independent mechanism of VEGF induction in colorectal tumor cells.
Röhrl
Clemens
C
Department of Medicine 1, Clinic for Internal Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
Kaindl
Ulrike
U
Koneczny
Inga
I
Hudec
Xenia
X
Baron
David M
DM
König
Jürgen S
JS
Marian
Brigitte
B
D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics; D006801:Humans; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
C425931:GW 501516; D047494:PPAR delta; D047495:PPAR gamma; D048068:PPAR-beta; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C039671:ciglitazone