rpL3 mediates the cell response to nucleolar stress induced by Act D in p53 null cancer cells

Many chemotherapeutic drugs impair ribosomal biogenesis causing nucleolar stress and p53-independent pathways mediating the nucleolar stress response are emerging. Here, we demonstrate that nucleolar stress induced by Actinomycin D is associated to the up-regulation of ribosomal protein L3 (rpL3) and its dissociation from the ribosome in lung and colon cancer cell lines lacking p53. We show that rpL3 is involved in drug-induced apoptosis and inhibition of cell proliferation and migration by controlling p21 expression both at transcriptional and post-translational levels. Depletion of rpL3 abolishes the cytotoxic effects of Act D while rpL3 overexpression was associated to a strong increase of Act D-mediated inhibition of cell migration. We identified extracellular-signal-regulated kinases1/2 (ERK1/2) and mouse double minute-2 homolog (MDM2) as new molecular targets involved in rpL3-mediated molecular pathways activated by Act D in cancers lacking of p53. Taking together our results show that the efficacy of Act D chemotherapy depends on rpL3 status. Hence, the development of treatments aimed at upregulating rpL3 may be beneficial for the treatment of these cancers.