Aproteasome-p27 system is involved in growth inhibition by PPARγ ligands in GI cancers

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We have demonstrated that peroxisome proliferator activated receptor gamma(PPARr) ligands inhibit cell growth in gastric and pancreatic cancer cells and that p27 accumulation is essential for the growth inhibition by PPAR ligands(Takahashi et al., FEBS Lett 1999,Motomura et al., Cancer Res 2000). In the present study, we tried to clarify the precise mechanisms by which PPAR ligand stimulates the protein expression of p27. Troglitazone, a ligand for PPAR, increased the protein amount of p27 and inhibited cell growth in gastric, pancreatic and hepatic cancer cells. Lactacystin, an proteasome inhibitor, by itself similarly inhibited cell growth and increased p27 protein expression. Troglitazone potently inhibited proteasome activity. These results suggest that PPAR activation by troglitazone inhibits proteasome activity, thereby accumulating p27 protein, which in turn inhibits cell growth. We furthermore demonstrated that troglitazone suppressed skp2, an ubiqutin ligaze, expression. All these results suggest that the growth inhibition by PPAR actibvation was mediated by p27^<Kip1> accumulation which is induced by both inhibition of ubiquitylation of p27^<Kip1> and reduction of degradation activity of p27^<Kip1> by proteasome.