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.

Type I interferon-mediated pathway interacts with peroxisome proliferator activated receptor-γ (PPAR-γ) : at the cross-road of pancreatic cancer cell proliferation / A. Dicitore, M. Caraglia, G. Gaudenzi, G. Manfredi, B. Amato, D. Mari, L. Persani, C. Arra, G. Vitale. - In: BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER. - ISSN 0304-419X. - 1845:1(2014 Jan), pp. 42-52.

Type I interferon-mediated pathway interacts with peroxisome proliferator activated receptor-γ (PPAR-γ) : at the cross-road of pancreatic cancer cell proliferation

G. Gaudenzi;D. Mari;L. Persani;G. Vitale
Ultimo
2014

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.
JAK-2/STAT-3 pathway; Pancreatic adenocarcinoma; PPAR-γ; Type I interferon; Animals; Cell Proliferation; Humans; Interferon Type I; Interferon-beta; PPAR gamma; Pancreatic Neoplasms; Signal Transduction; Oncology; Cancer Research; Genetics
Settore MED/13 - Endocrinologia
Settore MED/09 - Medicina Interna
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/244412
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