microRNA-494 and ATF3 the targets of onconase(?)

Onconase (Onc; also named ranpirnase), a 12 kD ribonuclease from oocytes of northern leopard frogs (Rana pipiens), is cytostatic and cytotoxic to variety tumor cell lines, inhibits growth of tumors in model animals and advanced to clinical trials as anticancer and antiviral drug [1]. Although its cytostatic and cytotoxic properties were recognized nearly three decades ago [2] mechanism of action is still elusive. The anticancer properties of Onc require its ribonucleolytic activity sustained by resistance to ribonuclease inhibitor protein that is present in cytosol as well as to its remarkable conformational stability. However, it is unclear which RNA species are preferential Onc targets whose destruction may explain anticancer specificity of this RNase. The initial observation that rRNA and tRNA become degraded in Onc-treated cells led the authors to propose that suppression of translation is the primary cause of its activity. However subsequent observations of cells sensitivity to Onc, its effect on the cell cycle, and complexity of other effects that lead to cell death were incompatible with this notion. In fact the evidence was accumulating that different signaling pathways become activated and diverse genes were up-and down-regulated [3]. In this issue of Oncotarget Vert et al., [4] report on their attempts to identify the Onc regulated genes that could explain the cytotoxic and anticancer properties of this RNase. Using the microarray-derived transcriptional profiling, confirmed by RT-qPCR, they noticed that among the up-regulated genes the most conspicuous is activating transcription factor 3 (ATF3). This was the case for both ovarian cancer cell lines analyzed by the authors. Together with up-regulation of several genes downstream of ATF3, the character of cell cycle changes and other effects leading to cell apoptosis, the data suggest that activation of ATF3 is the key event responsible for cytotoxicity of Onc and for its specificity to cancer cells. Also the prior studies [3] exploring the up-and down-regulation of different genes by Onc in malignant mesothelioma cell lines, conform to these findings. The reported data are also congruent with the observed antiviral properties of Onc in as much as this transcription factor can be implicated in suppressing viral genome replication, keeping virus latency or preventing viral oncogenesis [4]. The findings that ATF3 is the Onc target are in accordance with earlier reports that activation of ATF3 by other than Onc means triggers signaling pathways that lead to apoptosis in different types of cancers. Of particular interest are observations …