Interferon-lambda 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-lambdas) 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-lambda1 with nine human oesophageal carcinoma cell lines expressing the IFN-lambda receptor complexes. Among them, three lines but not others showed IFN-lambda1-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-lambda1 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-lambda1-induced growth suppression. IFN-lambda1 produced combinatory anti-tumour effects with chemotherapeutic agents, cisplatin (CDDP) and 5-fluorouracil (5-FU), in IFN-lambda1-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-lambda1 responsiveness is tissue-specific due to the restricted receptors expression and is diversified even among cells of the same lineage, and suggest that IFN-lambda1 is a potential therapeutic agent for oesophageal carcinoma without damaging surrounding tissues.
Li
Quanhai
Q
Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan.
Kawamura
Kiyoko
K
Ma
Guangyu
G
Iwata
Fumi
F
Numasaki
Muneo
M
Suzuki
Nobuo
N
Shimada
Hideaki
H
Tagawa
Masatoshi
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007372:Interferons; D053710:Interleukin-10 Receptor beta Subunit / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology*; D018121:Receptors, Cytokine / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured; D000095022:Interferon Lambda
D007372:Interferons; D053710:Interleukin-10 Receptor beta Subunit; D007378:Interleukins; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C081846:IL10RB protein, human; C471046:interleukin 28alpha receptor