Therapeutic dosages of aspirin counteract the IL-6 induced pro-tumorigenic effects by slowing down the ribosome biogenesis rate

// Elisa Brighenti 1 , Ferdinando Antonino Giannone 2, 3 , Francesca Fornari 3 , Carmine Onofrillo 1 , Marzia Govoni 1 , Lorenzo Montanaro 1 , Davide Treré 1 , Massimo Derenzini 1 1 Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40138, Italy 2 Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy 3 Biomedical and Applied Research Center, University Hospital of Bologna, Policlinico S. Orsola-Malpighi, Bologna 40138, Italy Correspondence to: Massimo Derenzini, email: massimo.derenzini@unibo.it Keywords: aspirin, inflammation, cancer, ribosome biogenesis, p53 Received: March 23, 2016 Accepted: August 13, 2016 Published: August 20, 2016 ABSTRACT Chronic inflammation is a risk factor for the onset of cancer and the regular use of aspirin reduces the risk of cancer development. Here we showed that therapeutic dosages of aspirin counteract the pro-tumorigenic effects of the inflammatory cytokine interleukin(IL)-6 in cancer and non-cancer cell lines, and in mouse liver in vivo . We found that therapeutic dosages of aspirin prevented IL-6 from inducing the down-regulation of p53 expression and the acquisition of the epithelial mesenchymal transition (EMT) phenotypic changes in the cell lines. This was the result of a reduction in c-Myc mRNA transcription which was responsible for a down-regulation of the ribosomal protein S6 expression which, in turn, slowed down the rRNA maturation process, thus reducing the ribosome biogenesis rate. The perturbation of ribosome biogenesis hindered the Mdm2-mediated proteasomal degradation of p53, throughout the ribosomal protein-Mdm2-p53 pathway. P53 stabilization hindered the IL-6 induction of the EMT changes. The same effects were observed in livers from mice stimulated with IL-6 and treated with aspirin. It is worth noting that aspirin down-regulated ribosome biogenesis, stabilized p53 and up-regulated E-cadherin expression in unstimulated control cells also. In conclusion, these data showed that therapeutic dosages of aspirin increase the p53-mediated tumor-suppressor activity of the cells thus being in this way able to reduce the risk of cancer onset, either or not linked to chronic inflammatory processes.