Attenuation of Peroxisome Proliferator-activated Receptor γ (PPARγ) Mediates Gastrin-stimulated Colorectal Cancer Cell Proliferation

Abstract

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.

Concomitant supplementation of lycopene and eicosapentaenoic acid inhibits the proliferation of human colon cancer cells

“…Cells were lysed in a buffer containing: 1× PBS, 1% Ipegal CA-630 (Sigma), 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate (SDS) with 100 μM of phenylmethylsulfonyl fluoride, aprotinin and specific phosphatase inhibitors, and sodium orthovanadate. Nuclear proteins were prepared as briefly described in the previous study [33]. Cellular proteins (100 μg) were fractioned on 10% SDS polyacrylamide gel electrophoresis (SDS-PAGE), transferred to nitrocellulose membrane, and blotted with antiphosphorylation Akt polyclonal antibody, according to the manufacturer's instructions.…”

“…Peroxisome proliferators-activated receptor γ (PPARγ) is a ligandactivated transcription factor belonging to the steroid/thyroid receptor superfamily and plays a critical role in the control of adipogenesis [31,32]. PPARγ has also been shown to suppress cell proliferation and tumorigenesis of various types of cancer [33][34][35][36]. N-3 PUFA might modulate PPARγ expression and mediate cell death [37,38].…”

Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion

“…Previous studies have reported that the stimulation of the CCK2R by its agonist ligands activates various signal transduction pathways implicated in cell proliferation, including phospholipase C, mitogen-activated protein kinases, expression of early growth-responsive genes, and activation of ornithine decarboxylase (ODC) ( 6 ). More recently, gastrin has been shown to activate cell proliferation in colorectal tumors by a mechanism involving the phosphorylation and degradation of the nuclear receptor peroxisome proliferator-activated receptor ␥ , a transcriptional factor reported to lower cholesterol metabolism when activated by agonist ligands ( 22 ). A link between CCK2R activation and the regulation of cholesterol metabolism has recently been reported in neuronal cells.…”

MAPK- Kinases as Nucleo-Cytoplasmic Shuttles for PPARγ

“…Poly-ubiquitination and proteasomal Poly-ubiquitination and proteasomal degradation upon S82/112 phosphorylation of PPARγ is evoked by IFNγ in adipocytes, 45,46 Her-2 in breast, 47 and gastrin in colorectal gastrin in colorectal colorectal olorectal cancer cells. 48 Inhibition of PPARγ phosphorylation by either stable introduction of a PPARγ S82A mutant or the use of LMW-inhibitors promotes terminal differentiation of NIH-3T3 fibroblasts to the adipogenic lineage, 37 and human epithelial breast cancer cells. 49 Mice with a knocked-in mutated S82/112A allele in the PPARγ locus exhibit resistance to diet-induced obesity, underlining a physiological role for MAPK-mediated S82/112 phosphorylation in inactivation of the genomic PPARγ action in vivo.…”