Therapeutic dosages of aspirin counteract the IL-6 induced pro-tumorigenic effects by slowing down the ribosome biogenesis rate
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Elisa Brighenti1, Ferdinando Antonino Giannone2,3, Francesca Fornari3, Carmine Onofrillo1, Marzia Govoni1, Lorenzo Montanaro1, Davide Treré1, Massimo Derenzini1
1Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna 40138, Italy
2Department of Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy
3Biomedical and Applied Research Center, University Hospital of Bologna, Policlinico S. Orsola-Malpighi, Bologna 40138, Italy
Massimo Derenzini, email: [email protected]
Keywords: aspirin, inflammation, cancer, ribosome biogenesis, p53
Received: March 23, 2016 Accepted: August 13, 2016 Published: August 20, 2016
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.
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