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

Anticancer Res. 2008 Mar-Apr;28(2A):895-906.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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