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PMID: 17148604 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 50 ·2006-12-12 ·Pages 19069-74

Wang D, Wang H, Guo Y, Ning W, Katkuri S, Wahli W, Desvergne B, Dey SK, DuBois RN

Abstract

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.

MeSH Terms
Adenoma/genetics,metabolism,pathology Animals Cell Line, Tumor Cell Survival Disease Progression Enzyme Activation Female Gene Expression Regulation, Neoplastic Humans Intestinal Neoplasms/genetics,metabolism,pathology Intestinal Polyps/chemically induced,genetics,metabolism,pathology Male Mice Mice, Knockout PPAR delta/deficiency,genetics,metabolism Proto-Oncogene Proteins c-akt/metabolism Thiazoles/pharmacology Vascular Endothelial Growth Factor A/metabolism
Chemicals
GW 501516 PPAR delta Thiazoles Vascular Endothelial Growth Factor A Proto-Oncogene Proteins c-akt
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Wang Dingzhi
Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, TN 37232-2279, USA.
Wang Haibin
Guo Yong
Ning Wei
Katkuri Sharada
Wahli Walter
Desvergne Beatrice
Dey Sudhansu K
DuBois Raymond N
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0607948103
Published
2006-12-12
Epub
2006-00-05
Pages
19069-74
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1748178
Subset
IM
Grants
NCI NIH HHS · P01 CA 77839 · United States
NIDDK NIH HHS · R01 DK 62112 · United States
NICHD NIH HHS · R37 HD 12304 · United States
NIDDK NIH HHS · R37 DK 47297 · United States
NICHD NIH HHS · P30 HD033994 · United States
NICHD NIH HHS · R37 HD012304 · United States
NCI NIH HHS · P01 CA077839 · United States
NCI NIH HHS · P30 CA 068485 · United States
NCI NIH HHS · P30 CA068485 · United States
NIDDK NIH HHS · R37 DK047297 · United States
NIDDK NIH HHS · R01 DK062112 · United States
NICHD NIH HHS · U54 HD033994 · United States
External Links
PubMed source DOI: 10.1073/pnas.0607948103 PMC Full Text View journal details
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