Wang Dingzhi, Wang Haibin, Guo Yong, Ning Wei, Katkuri Sharada, Wahli Walter, Desvergne Beatrice, Dey Sudhansu K, DuBois Raymond N
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN 37232-2279, USA.
Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19069-74. doi: 10.1073/pnas.0607948103. Epub 2006 Dec 5.
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.
过氧化物酶体增殖物激活受体（PPAR）δ是核激素受体超家族的成员。PPARδ可能改善肥胖和糖尿病等代谢性疾病。然而，PPARδ在结直肠癌发生中的作用仍存在争议。在此，我们提供遗传学和药理学证据表明，PPARδ的缺失会减少Apc(Min/+)小鼠肠道腺瘤的生长，并抑制PPARδ激动剂GW501516的促肿瘤作用。更重要的是，我们发现PPARδ的激活上调了结肠癌细胞中的血管内皮生长因子（VEGF）。VEGF通过激活PI3K-Akt信号通路直接促进结肠肿瘤上皮细胞的存活。这些结果不仅凸显了对PPARδ激动剂用于治疗结直肠癌高危患者代谢紊乱的担忧，也支持了开发PPARδ拮抗剂用于预防和/或治疗癌症的理论依据。
