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.

Abstract

BACKGROUND:

Caveolin-1, a key component of plasma membrane caveolae, has been implicated in the regulation of cancer cell growth and survival. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated nuclear receptor which plays a pivotal role in many cellular processes. Activation of PPARgamma by its ligand rosiglitazone upregulates caveolin-1 mRNA and protein in human carcinoma cells.

MATERIALS AND METHODS:

We have used specific signaling inhibitors to dissect the mechanisms of caveolin-1 mRNA and protein induction by rosiglitazone, determined by RT-PCR and Western blotting, respectively. ROS generation was measured by flow cytometry and cell survival was determined by the MTT assay.

RESULTS:

We show that in HT-29 human colon cancer cells the induction ofcaveolin-1 by rosiglitazone is inhibited by the EGF receptor (EGFR) blocker AG1478. Moreover, rosiglitazone stimulates EGFR phosphorylation, while direct activation of EGFR by EGF up-regulates caveolin-1 mRNA. Inhibitors of Src and the Mek1-Erk1/2 and p38 MAP kinase pathways also inhibit up-regulation of caveolin-1 by rosiglitazone. Furthermore, rosiglitazone stimulates formation of superoxide anions, whereas induction of caveolin-1 expression by rosiglitazone is attenuated by the antioxidant N-acetyl-cysteine. Finally, rosiglitazone increases the resistance of HT-29 cells to doxorubicin and to hydrogen peroxide. The caveolin-1 gene promoter lacks a canonical PPARgamma response element (PPRE) and a PPRE-reporter construct is not sensitive to EGF or EGFR inhibition.

CONCLUSION:

Our findings indicate that up-regulation of caveolin-1 by rosiglitazone requires superoxide formation and the activation of Src, EGFR, and the Mek1-Erk1/2 and p38 MAP kinase pathways. We suggest a novel mode of action of PPARgamma ligands in the regulation of caveolin-1, and possibly other genes devoid of a PPRE in their promoters, which involves the coordinate activation of PPARgamma and intracellular signaling pathways.

• Authors: Lilach Tencer, Elke Burgermeister, Matthias P Ebert, Mordechai Liscovitch
• Journal: Anticancer research (Anticancer Res) 2008 Mar-Apr Vol. 28 Issue 2A Pg. 895-906 ISSN: 0250-7005 [Print] Greece
• PMID: 18507034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caveolin 1
• PPAR gamma
• RNA, Messenger
• Reactive Oxygen Species
• Thiazolidinediones
• Rosiglitazone
• Superoxides
• Epidermal Growth Factor
• ErbB Receptors

Topics

• Caveolin 1 (metabolism)
• Cell Survival
• Drug Resistance, Neoplasm
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (physiology)
• HT29 Cells
• Humans
• PPAR gamma (antagonists & inhibitors, pharmacology)
• RNA, Messenger (metabolism)
• Reactive Oxygen Species (metabolism)
• Rosiglitazone
• Signal Transduction
• Superoxides (metabolism)
• Thiazolidinediones (pharmacology)