title: 5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine-β-synthase in colon cancer cells lacking p53.
abstract: Recent findings revealed in cancer cells novel stress response pathways, which in response to many chemotherapeutic drugs causing nucleolar stress, will function independently from tumor protein p53 (p53) and still lead to cell cycle arrest and/or apoptosis. Since it is known that most cancers lack functional p53, it is of great interest to explore these emerging molecular mechanisms. Here, we demonstrate that nucleolar stress induced by 5-fluorouracil (5-FU) in colon cancer cells devoid of p53 leads to the activation of ribosomal protein L3 (rpL3) as proapoptotic factor. rpL3, as ribosome-free form, is a negative regulator of cystathionine-β-synthase (CBS) expression at transcriptional level through a molecular mechanism involving Sp1. The rpL3-CBS association affects CBS stability and, in addition, can trigger CBS translocation into mitochondria. Consequently apoptosis will be induced through the mitochondrial apoptotic cell death pathway characterized by an increased ratio of Bax to Bcl-2, cytochrome c release and subsequent caspase activation. It is noteworthy that silencing of CBS is associated to a strong increase of 5-FU-mediated inhibition of cell migration and proliferation. These data reveal a novel mechanism to accomplish p53-independent apoptosis and suggest a potential therapeutic approach aimed at upregulating rpL3 for treating cancers lacking p53.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pagliara
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Saide
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Mitidieri
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: d'Emmanuele di Villa Bianca
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sorrentino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Russo
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Annapina
authors.initials: A
authors.lastname: Russo
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D005472:Fluorouracil / Q000494:pharmacology*; D016158:Genes, p53; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; C494826:BAX protein, human; C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C000716547:RPL3 protein, human; D000090822:Ribosomal Protein L3; D012269:Ribosomal Proteins; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases; D003541:Cystathionine beta-Synthase; D005472:Fluorouracil
keywords: CBS; apoptosis; colon cancer; nucleolar stress; p53