Molecular Mechanism of the Antiproliferative Activity of Short Immunostimulating dsRNA.

Small double-stranded RNAs with certain sequence motifs are able to interact with pattern-recognition receptors and activate the innate immune system. Recently, we identified a set of short double-stranded 19-bp RNA molecules with 3-nucleotide 3'-overhangs that exhibited pronounced antiproliferative activity against cancer cells , and antitumor and antimetastatic activities in mouse models . The main objectives of this study were to identify the pattern recognition receptors that mediate the antiproliferative action of immunostimulating RNA (isRNA). Two cell lines, epidermoid carcinoma KB-3-1 cells and lung cancer A549 cells, were used in the study. These lines respond to the action of isRNA by a decrease in the growth rate, and in the case of A549 cells, also by a secretion of IL-6. Two sets of cell lines with selectively silenced genes encoding potential sensors and signal transducers of isRNA action were obtained on the basis of KB-3-1 and A549 cells. It was found that the selective silencing of and genes blocked the antiproliferative effect of isRNA, both in KB-3-1 and A549 cells, whereas the expression of and was not required for the antiproliferative action of isRNA. It was shown that, along with and genes, the expression of also plays a role in isRNA mediated IL-6 synthesis in A549 cells. Thus, PKR and RIG-I sensors play a major role in the anti-proliferative signaling triggered by isRNA.