The PPAR-γ agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-β treated pancreatic cancer cells
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.
|Keywords||AKT, Autophagy, Cell cycle, MAPK, MTOR, PPAR gamma, Recombinant interferon beta, STATs, Troglitazone, Type I interferons|
|Persistent URL||dx.doi.org/10.1016/j.biotechadv.2011.08.001, hdl.handle.net/1765/34883|
Vitale, G., Zappavigna, S., Marra, M., Dicitore, A., Meschini, S., Condello, M., … Caraglia, M.. (2012). The PPAR-γ agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-β treated pancreatic cancer cells. Biotechnology Advances, 30(1), 169–184. doi:10.1016/j.biotechadv.2011.08.001