Crosstalk between peroxisome proliferator-activated receptor δ and VEGF stimulates cancer progression.

Peroxisome proliferator-activated receptor (PPAR) δ is a member of the nuclear hormone receptor superfamily. PPARδ may ameliorate metabolic diseases such as obesity and diabetes. However, PPARδ's role in colorectal carcinogenesis remains controversial. Here, we present genetic and pharmacologic evidence demonstrating that deletion of PPAR6 decreases intestinal adenoma growth in Apc^Min/+ mice and inhibits tumor-promoting effects of a PPARδ agonist GW501516. More importantly, we found that activation of PPAR& 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 PPAR6 agonists for treatment of metabolic disorders in patients who are at high risk for colorectat cancer, but also support the rationale for developing PPARδ antagonists for prevention and/or treatment of cancer. [ABSTRACT FROM AUTHOR]