Activating Transcription Factor 3 as a Regulator and Predictor of Cisplatin Response in Human Cancers

Activating Transcription Factor 3 as a Regulator and Predictor of Cisplatin Response in Human Cancers

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dc.contributor.author O'Brien, Anna
dc.date.accessioned 2012-01-05T16:54:56Z
dc.date.available 2012-01-05T16:54:56Z
dc.date.created 2012 en_US
dc.date.issued 2012-01-05
dc.identifier.uri http://hdl.handle.net/10393/20501
dc.description.abstract Platinum-based chemotherapies are effective agents in the treatment of a wide variety of human cancers. However, patients with recurrent disease can become resistant to platinum-based chemotherapy, leading to low overall survival rates. Activating transcription factor 3 (ATF3) is a stress-inducible gene that is a regulator of cisplatin-induced cytotoxicity. ATF3 protein expression was upregulated after cytotoxic doses of cisplatin treatment in a panel of cell lines. A chromatin immunoprecipitation assay showed that upon treatment with cisplatin, ATF3 directly bound to the CHOP gene promoter and this correlated with an increase in CHOP protein expression. In a 1200 compound library screen performed on cancer cell lines, disulfiram, a dithiocarbamate drug, was identified as an enhancer of the cytotoxic effects of cisplatin. This increased cytotoxic action was likely due to disulfiram and cisplatin’s ability to induce ATF3 independently through two separate mechanisms, namely the MAPK and integrated stress pathways. Furthermore, ATF3 protein and mRNA levels were variable amongst human ovarian and lung cancer tissues, suggesting the potential for basal expression of ATF3 to be predictive of cisplatin treatment response. Thus, understanding ATF3’s role in cisplatin-induced cytotoxicity will lead to novel therapeutic approaches that could improve this drug’s efficacy. en_US
dc.language.iso en en_US
dc.subject cisplatin en_US
dc.subject disulfiram en_US
dc.subject activating transcription factor 3 en_US
dc.subject combination therapy en_US
dc.subject cancer en_US
dc.title Activating Transcription Factor 3 as a Regulator and Predictor of Cisplatin Response in Human Cancers en_US
dc.faculty.department Biochimie, microbiologie et immunologie / Biochemistry, Microbiology and Immunology en_US
dc.contributor.supervisor Dimitroulakos, Jim
dc.embargo.terms immediate en_US
dc.degree.name MSc en_US
dc.degree.level masters en_US
dc.degree.discipline Médecine / Medicine en_US

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