Carcinogenesis, Vol 19, 49-53, Copyright © 1998 by Oxford University Press
RN DuBois, R Gupta, J Brockman, BS Reddy, SL Krakow and MA Lazar
Continuous use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the
relative risk of colorectal cancer in humans and decreases tumor yield in
rodents treated with carcinogens. One well documented target for NSAIDs is
prostaglandin endoperoxide synthase (cyclooxygenase) and two isoforms of
this enzyme have been identified, cyclooxygenase-1 (COX- 1) and
cyclooxygenase-2 (COX-2). COX enzymes produce eicosanoid products, some of
which have recently been shown to activate transcription mediated by the
nuclear hormone receptor peroxisome proliferator activated receptor gamma
(PPARgamma), whose expression is largely restricted to adipose tissue. The
present study was undertaken to determine if PPARgamma was expressed in
colonic tumors. PPARgamma messenger RNA (mRNA) and protein levels were
assayed in colonic tumors and normal adjacent mucosa, as well as in a
variety of human colon cancer cell lines. There was a marked increase in
PPARgamma RNA levels in four out of four of the colonic tumors compared to
paired normal mucosa, where little expression of PPARgamma was detected.
Western blotting analysis showed that PPARgamma protein was expressed in
four out of five colonic tumor samples. PPARgamma was also expressed in a
subset of polyps, and in certain human colon cancer cell lines as well.
Additionally, we were able to demonstrate that an eicosanoid, 15 deoxy-
delta12,14 PGJ2, transactivated transcription of a PPRE-driven promoter in
CaCo-2 cells. Thus, we have shown that PPARgamma gene and protein
expression is elevated in rodent colon tumors, in selected human colon
cancer cell lines and that the PPARgamma receptor is functional in CaCo- 2
cells. Since PPARgamma is a ligand-modulated transcription factor, it may
provide a novel target for chemopreventive strategies for colorectal
cancer.
ARTICLES
The nuclear eicosanoid receptor, PPARgamma, is aberrantly expressed in colonic cancers
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. duboisrn@aoi.com
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