title: ATOX1 gene silencing increases susceptibility to anticancer therapy based on copper ionophores or chelating drugs.
abstract: Copper is a catalytic cofactor required for the normal function of many enzymes involved in fundamental biological processes but highly cytotoxic when in excess. Therefore its homeostasis and distribution is strictly regulated by a network of transporters and intracellular chaperones. ATOX1 (antioxidant protein 1) is a copper chaperone that plays a role in copper homeostasis by binding and transporting cytosolic copper to ATPase proteins in the trans-Golgi network. In the present study the Caco-2 cell line, a colon carcinoma cell line, was used as an in vitro model to evaluate if ATOX1 deficiency could affect sensitivity to experimentally induced copper dyshomeostasis. Silencing of ATOX1 increased toxicity of a short treatment with a high concentration of Cu(2+). Copper ionophores, such as 5-chloro-8-hydroxyquinoline, induced a copper-dependent cell toxicity which was significantly potentiated after ATOX1 silencing. The copper chelator TPEN (N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine) produced a form of cell toxicity that was reversed by the addition of Cu(2+). ATOX1 silencing increased Caco-2 cell sensitivity to TPEN toxicity. Our results suggest the possibility of a therapy with copper-chelating or ionophore drugs in subtypes of tumors showing specific alterations in ATOX1 expression.
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Unit of Medical Biochemistry, University of Catania, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Barresi
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Unit of Medical Biochemistry, University of Catania, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Spampinato
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Unit of Medical Biochemistry, University of Catania, Italy.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Musso
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Unit of Medical Biochemistry, University of Catania, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Trovato Salinaro
authors.affiliation: Institute of Biostructures and Bioimaging, National Council of Research, UOS Catania, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Rizzarelli
authors.affiliation: Department of Biomedical and Biotechnological Sciences, Unit of Medical Biochemistry, University of Catania, Italy. Electronic address: daniele.condorelli@unict.it.
authors.forename: Daniele Filippo
authors.initials: DF
authors.lastname: Condorelli
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D000079922:Copper Transport Proteins; D020868:Gene Silencing; D006801:Humans; D056511:Metallochaperones / Q000235:genetics*; D018832:Molecular Chaperones; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C474500:ATOX1 protein, human; D000970:Antineoplastic Agents; D002614:Chelating Agents; D000079922:Copper Transport Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D012333:RNA, Messenger; D003300:Copper
keywords: ATOX1; Chelating drugs; Colon cancer; Copper; Ionophores