The PPAR-γ agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-β treated pancreatic cancer cells

Giovanni Vitale, Silvia Zappavigna, Monica Marra, Alessandra Dicitore, Stefania Meschini, Maria Condello, Giuseppe Arancia, Sara Castiglioni, Paola Maroni, Paola Bendinelli, Roberta Piccoletti, Peter M. Van Koetsveld, Francesco Cavagnini, Alfredo Budillon, Alberto Abbruzzese, Leo J. Hofland, Michele Caraglia

Research output: Contribution to journalArticlepeer-review


We have previously shown that cancer cells can protect themselves from apoptosis induced by type I interferons (IFNs) through a ras→MAPK-mediated pathway. In addition, since IFN-mediated signalling components STATs are controlled by PPAR gamma we studied the pharmacological interaction between recombinant IFN-β and the PPAR-γ agonist troglitazone (TGZ). This combination induced a synergistic effect on the growth inhibition of BxPC-3, a pancreatic cancer cell line, through the counteraction of the IFN-β-induced activation of STAT-3, MAPK and AKT and the increase in the binding of both STAT-1 related complexes and PPAR-γ with specific DNA responsive elements. The synergism on cell growth inhibition correlated with a cell cycle arrest in G0/G1 phase, secondary to a long-lasting increase of both p21 and p27 expressions. Blockade of MAPK activation and the effect on p21 and p27 expressions, induced by IFN-β and TGZ combination, were due to the decreased activation of STAT-3 secondary to TGZ. IFN-β alone also increased p21 and p27 expression through STAT-1 phosphorylation and this effect was attenuated by the concomitant activation of IFNbeta-induced STAT-3-activation. The combination induced also an increase in autophagy and a decrease in anti-autophagic bcl-2/beclin-1 complex formation. This effect was mediated by the inactivation of the AKT→mTOR-dependent pathway. To the best of our knowledge this is the first evidence that PPAR-γ activation can counteract STAT-3-dependent escape pathways to IFN-β-induced growth inhibition through cell cycle perturbation and increased autophagic death in pancreatic cancer cells.

Original languageEnglish
Pages (from-to)169-184
Number of pages16
JournalBiotechnology Advances
Issue number1
Publication statusPublished - Jan 2012


  • AKT
  • Autophagy
  • Cell cycle
  • MAPK
  • MTOR
  • PPAR gamma
  • Recombinant interferon beta
  • STATs
  • Troglitazone
  • Type I interferons

ASJC Scopus subject areas

  • Biotechnology


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