TY - JOUR
T1 - The PPAR-gamma agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-beta treated pancreatic cancer cells
AU - Vitale, G (Giovanni)
AU - Zappavigna, S
AU - Marra, M
AU - Dicitore, A
AU - Meschini, S
AU - Condello, M
AU - Arancia, G
AU - Castiglioni, S
AU - Maroni, P
AU - Bendinelli, P
AU - Piccoletti, R
AU - van Koetsveld, Peter
AU - Cavagnini, F
AU - Budillon, A
AU - Abbruzzese, A
AU - Hofland, Leo
AU - Caraglia, M
PY - 2012
Y1 - 2012
N2 - We have previously shown that cancer cells can protect themselves from apoptosis induced by type 1 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-beta and the PPAR-gamma 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-beta-induced activation of STAT-3, MAPK and AKT and the increase in the binding of both STAT-1 related complexes and PPAR-gamma 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-beta and TGZ combination, were due to the decreased activation of STAT-3 secondary to TGZ. 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-gamma activation can counteract STAT-3-dependent escape pathways to IFN-beta-induced growth inhibition through cell cycle perturbation and increased autophagic death in pancreatic cancer cells. (C) 2011 Elsevier Inc. All rights reserved.
AB - We have previously shown that cancer cells can protect themselves from apoptosis induced by type 1 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-beta and the PPAR-gamma 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-beta-induced activation of STAT-3, MAPK and AKT and the increase in the binding of both STAT-1 related complexes and PPAR-gamma 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-beta and TGZ combination, were due to the decreased activation of STAT-3 secondary to TGZ. 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-gamma activation can counteract STAT-3-dependent escape pathways to IFN-beta-induced growth inhibition through cell cycle perturbation and increased autophagic death in pancreatic cancer cells. (C) 2011 Elsevier Inc. All rights reserved.
U2 - 10.1016/j.biotechadv.2011.08.001
DO - 10.1016/j.biotechadv.2011.08.001
M3 - Article
C2 - 21871555
SN - 0734-9750
VL - 30
SP - 169
EP - 184
JO - Biotechnology Advances
JF - Biotechnology Advances
IS - 1
ER -
