Activating transcription factor 3 is crucial for antitumor activity and to strengthen the antiviral properties of Onconase.

// Anna Vert 1, 2 , Jessica Castro 1, 2 , Marc Ribo 1, 2 , Antoni Benito 1, 2 , Maria Vilanova 1, 2 1 Laboratori d’Enginyeria de Proteines, Departament de Biologia, Facultat de Ciencies, Universitat de Girona, Campus de Montilivi, 17003, Girona, Spain 2 Institut d’Investigacio Biomedica de Girona Josep Trueta, (IdIBGi), Girona, Spain Correspondence to: Maria Vilanova, email: maria.vilanova@udg.edu Antoni Benito, email: antoni.benito@udg.edu Keywords: antitumor and antiviral drug, Onconase, activating transcription factor 3, microarray profiling, apoptosis Received: June 04, 2016     Accepted: November 30, 2016     Published: December 27, 2016 ABSTRACT Onconase is a ribonuclease that presents both antitumor and antiviral properties linked to its ribonucleolytic activity and represents a new class of RNA-damaging drugs. It has reached clinical trials for the treatment of several cancers and human papilloma virus warts. Onconase targets different RNAs in the cell cytosol but Onconase-treated cells present features that are different from a simple arrest of protein synthesis. We have used microarray-derived transcriptional profiling to identify Onconase-regulated genes in two ovarian cancer cell lines (NCI/ADR-RES and OVCAR-8). RT-qPCR analyses have confirmed the microarray findings. We have identified a network of up-regulated genes implicated in different signaling pathways that may explain the cytotoxic effects exerted by Onconase. Among these genes, activating transcription factor 3 (ATF3) plays a central role in the key events triggered by Onconase in treated cancer cells that finally lead to apoptosis. This mechanism, mediated by ATF3, is cell-type independent. Up-regulation of ATF3 may also explain the antiviral properties of this ribonuclease because this factor is involved in halting viral genome replication, keeping virus latency or preventing viral oncogenesis. Finally, Onconase-regulated genes are different from those affected by nuclear-directed ribonucleases.