Abstract
Interferons (IFNs) have been tested for the therapeutic effects in various types of malignancy, but mechanisms of the anti-tumors effects and the differential biological activities among IFN members are dependent on respective cell types. In this study, we examined growth inhibitory activities of type I and III IFNs on 5 kinds of human mesothelioma cells bearing wild-type p53 gene, and showed that type I IFNs but not type III IFNs decreased the cell viabilities. Moreover, growth inhibitory activities and up-regulated expression levels of the major histocompatibility complexes class I antigens were greater with IFN-β than with IFN-α treatments. Cell cycle analyses demonstrated that type I IFNs increased S- and G2/M-phase populations, and subsequently sub-G1-phase fractions. The cell cycle changes were also greater with IFN-β than IFN-α treatments, and these data collectively showed that IFN-β had stronger biological activities than IFN-α in mesothelioma. Type I IFNs-treated cells increased p53 expression and the phosphorylation levels, and activated apoptotic pathways. A combinatory use of IFN-β and cisplatin or pemetrexed, both of which are the current first-line chemotherapeutic agents for mesothelioma, produced synergistic anti-tumor effects, which were also evidenced by increased sub-G1-phase fractions. These data demonstrated firstly to our knowledge that IFN-β produced synergistic anti-tumor effects with cisplatin or pemetrexed on mesothelioma through up-regulated p53 expression.
Highlights
Malignant mesothelioma, often linked with asbestos exposure, evokes serious social concerns in many countries, and the patient numbers in Western countries and newly industrializing economies will progressively increase in the decades [1,2]
Immortalized Met-5A cells expressed both of the type III receptor genes. These data collectively suggested that the mesothelioma cells could respond to type I IFNs but not to type III IFNs, whereas Met-5 cells could response to both IFNs
IFN-λ1 did not produce growth inhibitory effects in mesothelioma cells, whereas human esophageal carcinoma T.Tn cells, which were positive for both IL-28Rα and IL-10β [17], were sensitive to IFN-λ1 (Figure 2B & Table S1)
Summary
Often linked with asbestos exposure, evokes serious social concerns in many countries, and the patient numbers in Western countries and newly industrializing economies will progressively increase in the decades [1,2]. The current therapeutic strategy for the majority of mesothelioma cases is primarily chemotherapy, and a combinatory use of cisplatin (CDDP) and pemetrexed (PEM) is the first-line regimen [3]. The majority of mesothelioma has a deletion in the INK4A/ARF locus which encodes the p14ARF and the p16INK4A genes, but possesses the wild-type p53 gene [4]. Deletion of p16INK4A increases cyclindependent kinase 4/6 activities, which subsequently induces pRb phosphorylation and cell cycle progression. Deficiency of p14ARF augments Mdm activities and down-regulates p53 expression, which may render mesothelioma cells resistant to chemotherapeutic agents. Enhanced expression of p53 in mesothelioma is a possible therapeutic strategy by inducing cell cycle arrest and apoptosis [5]
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