title: Type I interferon-mediated pathway interacts with peroxisome proliferator activated receptor-γ (PPAR-γ): at the cross-road of pancreatic cancer cell proliferation.
abstract: Pancreatic adenocarcinoma remains an unresolved therapeutic challenge because of its intrinsically refractoriness to both chemo- and radiotherapy due to the complexity of signaling and the activation of survival pathways in cancer cells. Recent studies have demonstrated that the combination of some drugs, targeting most of aberrant pathways crucial for the survival of pancreatic cancer cells may be a valid antitumor strategy for this cancer. Type I interferons (IFNs) may have a role in the pathogenesis and progression of pancreatic adenocarcinoma, but the limit of their clinical use is due to the activation of tumor resistance mechanisms, including JAK-2/STAT-3 pathway. Moreover, aberrant constitutive activation of STAT-3 proteins has been frequently detected in pancreatic adenocarcinoma. The selective targeting of these cell survival cascades could be a promising strategy in order to enhance the antitumor effects of type I IFNs. The activation of peroxisome proliferator-activated receptor γ (PPAR-γ), on the other hand, has a suppressive activity on STAT-3. In fact, PPAR-γ agonists negatively modulate STAT-3 through direct and/or indirect mechanisms in several normal and cancer models. This review provides an overview on the current knowledge about the molecular mechanisms and antitumor activity of these two promising classes of drugs for pancreatic cancer therapy. Finally, the synergistic antiproliferative activity of combined IFN-β and troglitazone treatment on pancreatic cancer cell lines, evaluated in vitro, and the consequent potential clinical applications will be discussed.
authors.affiliation: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dicitore
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Germano
authors.initials: G
authors.lastname: Gaudenzi
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Manfredi
authors.affiliation: Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Amato
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Geriatric Unit IRCCS Ca' Grande Foundation Maggiore Policlinico Hospital, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Mari
authors.affiliation: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
authors.affiliation: Animal Facility, National Cancer Institute of Naples Fondazione "G. Pascale", Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.affiliation: Laboratory of Endocrine and Metabolic Research, Istituto Auxologico Italiano IRCCS, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Electronic address: giovanni.vitale@unimi.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vitale
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D016899:Interferon-beta / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007370:Interferon Type I; D047495:PPAR gamma; D016899:Interferon-beta
keywords: JAK-2/STAT-3 pathway; PPAR-γ; Pancreatic adenocarcinoma; Type I interferon