title: Metallothionein 1G and zinc sensitize human colorectal cancer cells to chemotherapy.
abstract: Metallothioneins (MT) are a family of low molecular weight proteins that are silenced during colorectal cancer progression, mainly through epigenetic mechanisms, and this loss is associated with poor survival. In this article, we show that overexpression of the MT1G isoform sensitizes colorectal cell lines to the chemotherapeutic agents oxaliplatin (OXA) and 5-fluorouracil (5-FU), in part through enhancing p53 and repressing NF-κB activity. Despite being silenced, MTs can be reinduced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate. In fact, this induction contributes to the cytotoxicity of these agents, given that silencing of MTs by siRNAs reduces their growth-inhibitory activities. Zinc ions also potently enhance MT expression and are cytotoxic to cancer cells. We show for the first time that OXA and 5-FU induce higher levels of intracellular labile zinc, as measured using the fluorescent probe FLUOZIN-3, and that such zinc contributes to the activation of p53 and repression of NF-κB. Addition of zinc enhanced growth inhibition by OXA and 5-FU, and was also capable of resensitizing 5-FU-resistant cell lines to levels comparable with sensitive cell lines. This effect was MT independent because silencing MTs did not affect zinc cytotoxicity. In conclusion, we show that MT induction and zinc administration are novel strategies to sensitize colorectal cancer cells to presently utilized chemotherapeutic agents.
authors.affiliation: Authors' Affiliations: Centro de Investigaciones Oncológicas de la Fundación Cáncer (CIO-FUCA); Laboratorio de Cancerología, Fundación Instituto Leloir, IIBBA-CONICET; Instituto Alexander Fleming, Buenos Aires, Argentina; and Operative Unit 'Molecular Mechanisms of Cancer Growth and Progression,' Department of Experimental Oncology, Fondazione IRCCS 'Istituto Nazionale dei Tumori,' Milan, Italy.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Arriaga
authors.forename: Angela
authors.initials: A
authors.lastname: Greco
authors.forename: José
authors.initials: J
authors.lastname: Mordoh
authors.forename: Michele
authors.initials: M
authors.lastname: Bianchini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D021381:Protein Transport; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C499629:MT1G protein, human; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D008668:Metallothionein; D015032:Zinc