A Novel Mechanism of PPAR Gamma Induction via EGFR Signalling Constitutes Rational for Combination Therapy in Bladder Cancer

Jose Joao Mansure, Roland Nassim, Simone Chevalier, Konrad Szymanski, Joice Rocha, Saad Aldousari, Wassim Kassouf

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: Two signalling molecules that are attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor gamma (PPARγ). We investigated possible crosstalk between these 2 pathways, particularly in light of the recent evidence implicating PPARγ for anticancer therapy. Principal Findings: As evaluated by MTT assays, gefitinib (EGFR inhibitor) and DIM-C (PPARγ agonist) inhibited growth of 9 bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. In addition, combination of gefitinib and DIM-C demonstrated maximal inhibition of cell proliferation compared to each drug alone. These findings were confirmed in vivo, where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p<0.04). Induction of PPARγ expression along with nuclear accumulation was observed in response to increasing concentrations of gefitinib via activation of the transcription factor CCAT/enhancer-binding protein-β (CEBP-β). In these cell lines, DIM-C significantly sensitized bladder cancer cell lines that were resistant to EGFR inhibition in a schedule-specific manner. Conclusion: These results suggest that PPARγ agonist DIM-C can be an excellent alternative to bladder tumors resistant to EGFR inhibition and combination efficacy might be achieved in a schedule-specific manner.

Original languageEnglish (US)
Article numbere55997
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 8 2013
Externally publishedYes

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PPAR gamma
Epidermal Growth Factor Receptor
Urinary Bladder Neoplasms
therapeutics
Cells
cell lines
Cell Line
agonists
Tumors
Appointments and Schedules
Therapeutics
Cell proliferation
Growth
Crosstalk
binding proteins
Assays
cell proliferation
Carrier Proteins
Transcription Factors
transcription factors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

A Novel Mechanism of PPAR Gamma Induction via EGFR Signalling Constitutes Rational for Combination Therapy in Bladder Cancer. / Mansure, Jose Joao; Nassim, Roland; Chevalier, Simone; Szymanski, Konrad; Rocha, Joice; Aldousari, Saad; Kassouf, Wassim.

In: PLoS One, Vol. 8, No. 2, e55997, 08.02.2013.

Research output: Contribution to journalArticle

Mansure, Jose Joao ; Nassim, Roland ; Chevalier, Simone ; Szymanski, Konrad ; Rocha, Joice ; Aldousari, Saad ; Kassouf, Wassim. / A Novel Mechanism of PPAR Gamma Induction via EGFR Signalling Constitutes Rational for Combination Therapy in Bladder Cancer. In: PLoS One. 2013 ; Vol. 8, No. 2.
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