Crosstalk between peroxisome proliferator-activated receptor delta and VEGF stimulates cancer progression.
Peroxisome proliferator-activated receptor (PPAR) delta is a member of the nuclear hormone receptor superfamily. PPARdelta may ameliorate metabolic diseases such as obesity and diabetes. However, PPARdelta's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPARdelta decreases intestinal adenoma growth in Apc(Min/+) mice and inhibits tumor-promoting effects of a PPARdelta agonist GW501516. More importantly, we found that activation of PPARdelta up-regulated VEGF in colon carcinoma cells. VEGF directly promotes colon tumor epithelial cell survival through activation of PI3K-Akt signaling. These results not only highlight concerns about the use of PPARdelta agonists for treatment of metabolic disorders in patients who are at high risk for colorectal cancer, but also support the rationale for developing PPARdelta antagonists for prevention and/or treatment of cancer.
Wang
Dingzhi
D
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN 37232-2279, USA.
Wang
Haibin
H
Guo
Yong
Y
Ning
Wei
W
Katkuri
Sharada
S
Wahli
Walter
W
Desvergne
Beatrice
B
Dey
Sudhansu K
SK
DuBois
Raymond N
RN
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D007417:Intestinal Polyps / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047494:PPAR delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C425931:GW 501516; D047494:PPAR delta; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt