Human rpL3 plays a crucial role in cell response to nucleolar stress induced by 5-FU and L-OHP

// Davide Esposito 1, 2 , Elvira Crescenzi 3 , Vinay Sagar 4 , Fabrizio Loreni 4 , Annapina Russo 5, * , Giulia Russo 5, * 1 Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Naples 80131, Italy 2 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 3 Institute of Experimental Endocrinology and Oncology-CNR, Naples 80131, Italy 4 Department of Biology, University of Rome ‘Tor Vergata’, Rome 00133, Italy 5 Department of Pharmacy, University of Naples “Federico II”, Naples 80131, Italy * These authors contributed equally to this publication and share last authorship Correspondence to: Giulia Russo, e-mail: giulia.russo@unina.it Annapina Russo, e-mail: annapina.russo@unina.it Keywords: p21, ribosomal protein, 5-FU, Oxaliplatin, DNA repair Received: August 18, 2014      Accepted: October 11, 2014      Published: November 28, 2014 ABSTRACT Recent evidence showed that a variety of DNA damaging agents including 5-FU and L-OHP impairs ribosomal biogenesis activating a ribosomal stress pathway. Here, we demonstrate that in lung and colon cancer cell lines devoid of p53, the efficacy of 5-FU and L-OHP chemotherapy depends on rpL3 status. Specifically, we demonstrate that ribosomal stress induced by 5-FU and L-OHP is associated to up-regulation of rpL3 and its accumulation as ribosome-free form. We show that rpL3 participates in the cell response to chemotherapy acting as a critical regulator of cell cycle, apoptosis and DNA repair, by modulating p21 expression. Moreover, we demonstrate that rpL3 is able to control DNA repair also independently from p21 status of cell. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of 5-FU and L-OH indicating that the loss of rpL3 makes chemotherapy drugs ineffective. Taking together our results shed light on 5-FU and L-OHP mechanism of action and contribute to more effective clinical use of these drugs in cancer therapy.