Interferon-λ induces G1 phase arrest or apoptosis in oesophageal carcinoma cells and produces anti-tumour effects in combination with anti-cancer agents

Signal pathways of novel type III interferons (IFN-lambda s) are similar to those of type I IFNs (IFN-alpha/beta) but their distinct functions have not been well characterised. We examined the growth suppressive activity of IFN-lambda 1 with nine human oesophageal carcinoma cell lines expressing the IFN-lambda receptor complexes. Among them, three lines but not others showed IFN-lambda 1-mediated growth suppression by inducing G1 phase arrest or apoptosis. The G1 phase arrest was accompanied by the up-regulation of p21 and dephosphorylation of retinoblastoma (Rb), and the apoptosis was evidenced by cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP). Similar but not identical susceptibility was found in IFN-alpha-treated oesophageal carcinoma cells. Despite the differential suppressive responses among the cells, all the cells increased the expression of the myxovirus resistance A (MxA) and 2',5'-oligoadenylate synthetase (2',5'-OAS) genes and class I antigens of the major histocompatibility complexes (MHC) with IFN-lambda 1 treatment. Fibroblasts and mesenchymal stem cells, positive for IFN-alpha receptor (IFNAR), lacked one of the IFN-lambda receptor complexes and Het-1A, immortalised oesophageal epithelium cells, were insensible to the IFN-lambda 1-induced growth suppression. IFN-lambda 1 produced combinatory anti-tumour effects with chemotherapeutic agents, cisplatin (CDDP) and 5-fluorouracil (5-FU), in IFN-lambda 1-sensitive oesophageal carcinoma cells but not in normal or Het-1A cells, while IFN-alpha achieved the combinatory suppressive effects to normal cells. These data collectively show that IFN-lambda 1 responsiveness is tissue-specific due to the restricted receptors expression and is diversified even among cells of the same lineage, and suggest that IFN-lambda 1 is a potential therapeutic agent for oesophageal carcinoma without damaging surrounding tissues. (C) 2009 Elsevier Ltd. All rights reserved.