Abstract
Interleukin 15 (IL-15) is a cytokine exhibiting antitumor characteristic similar to that of IL-2. However, in human tissues and cells, IL-15 expression and secretion is very limited, suggesting IL-15 functions mainly intracellularly. In the present study, we assessed the effects of transfecting NCI-H446 small cell lung cancer cells with genes encoding three IL-15 variants: prototypical IL-15, mature IL-15 peptide, and modified IL-15 in which the IL-2 signal peptide is substituted for the native signal peptide. NCI-H446 cells transfected with empty plasmid served as the control group. We found that IL-15 transfection effectively inhibited NCI-H446 cell proliferation and arrested cell cycle progression, with the modified IL-15 carrying the IL-2 signal peptide exerting the greatest effect. Consistent with those findings, expression each of the three IL-15 variants reduced growth of NCI-H446 xenograph tumors, and the modified IL-15 again showed the greatest effect. In addition, IL-15 expression led to down-regulation of the positive cell cycle regulators cyclin E and CDK2 and up-regulation of the negative cycle regulators p21 and Rb. These findings suggest IL-15 acts as a tumor suppressor that inhibits tumor cell proliferation by inducing cell cycle arrest.
Highlights
Among the new approaches to treating various cancers is gene therapy, in which the gene encoding an anti-tumor cytokine is transfected into the tumor cells [1, 2]
We initially transfected NCI-H446 cells with genes encoding three different Interleukin 15 (IL-15) variants: the CIL-15 group was transfected with the IL-15 prototype, the CIL-15mp group was transfected with mature IL-15 peptide, and the CIL-2sp-IL-15mp group was transfected with a modified IL-15 in which the IL-15 signal peptide was replaced with IL-2 signal peptide
These results suggest transfection with prototypical IL-15 effectively inhibited the NCI-H446 cell proliferation, but that effect was enhanced by transfection with modified IL-15 carrying the IL-2 signal peptide
Summary
Among the new approaches to treating various cancers is gene therapy, in which the gene encoding an anti-tumor cytokine is transfected into the tumor cells [1, 2]. IL-15 mRNA is readily detected in many kinds of cells and tissues, but secretion of the corresponding protein is rarely detected, which suggests IL-15 protein expression is controlled by posttranscriptional mechanisms – i.e., at the level of protein translation and intracellular trafficking [10,11,12,13,14,15,16,17,18]. Other data suggest IL-15 carries out its biological functions mainly intracellularly [19]. It was observed in nude mice inoculated with tumor cells that transfecting the cells with a gene encoding prototypical IL-15 did not yield a promising anti-tumor effect. It was suggested that the long signal peptide expressed with IL-15 acts as an inhibitor to IL-15 secretion; transcription of a modified IL-15 gene lacking the signal peptide did not substantially increase IL-15 secretion [20]
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