title: The PPAR-γ agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-β treated pancreatic cancer cells.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Mediche, Universita` degli Studi di Milano, Milan, Italy. giovanni.vitale@unimi.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitale
authors.forename: Silvia
authors.initials: S
authors.lastname: Zappavigna
authors.forename: Monica
authors.initials: M
authors.lastname: Marra
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dicitore
authors.forename: Stefania
authors.initials: S
authors.lastname: Meschini
authors.forename: Maria
authors.initials: M
authors.lastname: Condello
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Arancia
authors.forename: Sara
authors.initials: S
authors.lastname: Castiglioni
authors.forename: Paola
authors.initials: P
authors.lastname: Maroni
authors.forename: Paola
authors.initials: P
authors.lastname: Bendinelli
authors.forename: Roberta
authors.initials: R
authors.lastname: Piccoletti
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavagnini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Budillon
authors.forename: Alberto
authors.initials: A
authors.lastname: Abbruzzese
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D004273:DNA, Neoplasm; D047495:PPAR gamma; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D045162:Thiazolidinediones; D016899:Interferon-beta; D020929:Mitogen-Activated Protein Kinase Kinases; D000077288:Troglitazone