title: Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53.
abstract: Many chemotherapeutic drugs cause nucleolar stress and p53-independent pathways mediating the nucleolar stress response are emerging. Here, we demonstrate that ribosomal stress induced by Actinomycin D (Act D) is associated to the up-regulation of ribosomal protein L3 (rpL3) and its accumulation as ribosome-free form in lung and colon cancer cell lines devoid of p53. Free rpL3 regulates p21 expression at transcriptional and post-translational levels through a molecular mechanism involving extracellular-signal-regulated kinases1/2 (ERK1/2) and mouse double minute-2 homolog (MDM2). Our data reveal that rpL3 participates to cell response acting as a critical regulator of apoptosis and cell migration. It is noteworthy that silencing of rpL3 abolishes the cytotoxic effects of Act D suggesting that the loss of rpL3 makes chemotherapy drugs ineffective while rpL3 overexpression associates to a strong increase of Act D-mediated inhibition of cell migration. Taking together our results show that the efficacy of Act D chemotherapy depends on rpL3 status revealing new specific targets involved in the molecular pathways activated by Act D in cancers lacking of p53. Hence, the development of treatments aimed at upregulating rpL3 may be beneficial for the treatment of these cancers.
authors.affiliation: a Department of Pharmacia , University of Naples "Federico II," ; Naples , Italy.
authors.forename: Annapina
authors.initials: A
authors.lastname: Russo
authors.affiliation: a Department of Pharmacia , University of Naples "Federico II," ; Naples , Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pagliara
authors.affiliation: a Department of Pharmacia , University of Naples "Federico II," ; Naples , Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Albano
authors.affiliation: b Department of Molecular Medicine and Medical Biotechnology , University of Naples "Federico II," Naples , Italy.|c Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Esposito
authors.affiliation: d Department of Biology , University of Rome "Tor Vergata," Rome , Italy.
authors.forename: Vinay
authors.initials: V
authors.lastname: Sagar
authors.affiliation: d Department of Biology , University of Rome "Tor Vergata," Rome , Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loreni
authors.affiliation: a Department of Pharmacia , University of Naples "Federico II," ; Naples , Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Irace
authors.affiliation: a Department of Pharmacia , University of Naples "Federico II," ; Naples , Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Santamaria
authors.affiliation: a Department of Pharmacia , University of Naples "Federico II," ; Naples , Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Russo
mesh_terms: D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003609:Dactinomycin / Q000633:toxicity*; D045325:HCT116 Cells; D006801:Humans; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins / Q000502:physiology*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
chemical_list: C000716547:RPL3 protein, human; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; C000716548:Rpl3 protein, mouse; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin
keywords: Actinomycin D; ERK; MDM2; apoptosis; cancer; nucleolar stress; p21; p53; ribosomal protein