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J. Biol. Chem., Vol. 281, Issue 21, 14700-14710, May 26, 2006

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Attenuation of Peroxisome Proliferator-activated Receptor (PPAR) Mediates Gastrin-stimulated Colorectal Cancer Cell Proliferation^*

From the Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118

Peroxisome proliferators-activated receptor (PPAR) has been shown to suppress cell proliferation and tumorigenesis, whereas the gastrointestinal regulatory peptide gastrin stimulates the growth of neoplastic cells. The present studies were directed to determine whether changes in PPAR expression might mediate the effects of gastrin on the proliferation of colorectal cancer (CRC). Initially, using growth assays, we determined that the human CRC cell line DLD-1 expressed both functional PPAR and gastrin receptors. Amidated gastrin (G-17) attenuated the growth suppressing effects of PPAR by decreasing PPAR activity and total protein expression, in part through an increase in the rate of proteasomal degradation. G-17-induced degradation of PPAR appeared to be mediated through phosphorylation of PPAR at serine 84 by a process involving the biphasic phosphorylation of ERK1/2 and activation of the epidermal growth factor receptor (EGFR). These results were confirmed through the use of EGFR antagonist AG1478 and MEK1 inhibitor PD98059. Furthermore, mutation of PPAR at serine 84 reduced the effects of G-17, as evident by inability of G-17 to attenuate PPAR promoter activity, degrade PPAR, or inhibit the growth suppressing effects of PPAR. The results of these studies demonstrate that the trophic properties of gastrin in CRC may be mediated in part by transactivation of the EGFR and phosphorylation of ERK1/2, leading to degradation of PPAR protein and a decrease in PPAR activation.

Received for publication, March 20, 2006

^* This study was supported by Grants R01 CA118992 (to M. M. W.) and F32 DK67812 from the National Institutes of Health (to D. H. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Section of Gastroenterology, Boston Medical Center, 650 Albany St., Rm. 504, Boston, MA 02118. Tel.: 617-638-8330; Fax: 617-638-7785; E-mail: michael.wolfe{at}bmc.org.

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