ATOX1 gene silencing increases susceptibility to anticancer therapy based on copper ionophores or chelating drugs

作者：Barresi Vincenza; Spampinato Giorgia; Musso Nicolo; Salinaro Angela Trovato; Rizzarelli Enrico; Condorelli Daniele Filippo^*

来源：Journal of Inorganic Biochemistry, 2016, 156: 145-152.

DOI：10.1016/j.jinorgbio.2016.01.002

• Copper
• ATOX1
• Colon cancer
• Chelating drugs
• Ionophores

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 Cu2+. 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 Cu2+. 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.

• 出版日期2016-3