Rosiglitazone induces caveolin-1 by PPARgamma-dependent and PPRE-independent mechanisms: the role of EGF receptor signaling and its effect on cancer cell drug resistance.

摘要: BACKGROUND: Caveolin-1, a key component of plasma membrane caveolae, has been implicated in the regulation cancer cell growth and survival. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is ligand-activated nuclear receptor which plays pivotal role many cellular processes. Activation PPARgamma by its ligand rosiglitazone upregulates caveolin-1 mRNA protein human carcinoma cells. MATERIALS AND METHODS: We have used specific signaling inhibitors to dissect mechanisms induction rosiglitazone, determined RT-PCR Western blotting, respectively. ROS generation was measured flow cytometry survival MTT assay. RESULTS: show that HT-29 colon cells ofcaveolin-1 inhibited EGF (EGFR) blocker AG1478. Moreover, stimulates EGFR phosphorylation, while direct activation up-regulates mRNA. Inhibitors Src Mek1-Erk1/2 p38 MAP kinase pathways also inhibit up-regulation rosiglitazone. Furthermore, formation superoxide anions, whereas expression attenuated antioxidant N-acetyl-cysteine. Finally, increases resistance doxorubicin hydrogen peroxide. The gene promoter lacks canonical response element (PPRE) PPRE-reporter construct not sensitive or inhibition. CONCLUSION: Our findings indicate requires Src, EGFR, pathways. suggest novel mode action ligands caveolin-1, possibly other genes devoid PPRE their promoters, involves coordinate intracellular