Role of the transcription factor Ets-1 in cisplatin resistance.
Cisplatin is a DNA damaging agent widely used as a chemotherapeutic agent. A major limitation of the use of this agent is the development of drug resistance within tumors. Several in vitro models exist which enable the investigation of resistance mechanisms, including 2008/C13* ovarian carcinoma cells. C13* cells are variants of 2008 cells, displaying cisplatin resistance following 13 consecutive cisplatin treatments. This model system has led to the identification of several mechanisms that play parts in the multifactorial nature of cisplatin resistance. In this study, we have examined the contribution of a transcription factor, Ets-1, to the cisplatin resistance of C13* cells. Ets-1 is up-regulated in C13* cells as compared with the cisplatin-sensitive 2008 cells and overexpression of this protein in 2008 cells led to a 7-fold increase in resistance. Further studies on a colorectal carcinoma cell line overexpressing Ets-1 indicated that this phenomenon is not cell specific-increased cisplatin resistance correlated to Ets-1 expression. The mechanism of cisplatin resistance elicited by Ets-1 is potentially via transcriptional activation of genes whose products have well-described functions in reducing cisplatin toxicity. Examples, identified via microarray analysis, include metallothioneins and DNA repair enzymes. This is the first report to our knowledge associating expression of Ets-1, a transcription factor whose expression often signals poor prognosis in various cancer types, to cisplatin resistance.
Wilson
Leigh A
LA
Juravinski Cancer Center and Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.
Yamamoto
Hirotaka
H
Singh
Gurmit
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D002945:Cisplatin