We employed
cDNA microarrays to identify the differentially expressed genes in a
cisplatin-sensitive parental (2008) human ovarian
carcinoma cell line and its
cisplatin-resistant variant (2008/C13*). Differential expression of five genes was found in the 2008/C13* cells, a result confirmed by semi-quantitative reverse transcription-PCR. The five genes were identified as fibroblast muscle-type
tropomyosin and skeletal muscle-type
tropomyosin,
dihydrodiol dehydrogenase,
apolipoprotein J and
glucose-6-phosphate dehydrogenase variant-A. Treatment of the 2008 cells with
cisplatin (at its IC(50) concentration of 2 microm) induced expression of these genes, as determined by semi-quantitative reverse transcription-PCR analysis using gene-specific primers. In contrast, treatment of the
drug-resistant 2008/C13* cells with
cisplatin (at its IC(50) concentration of 20 microm) did not lead to the induction of any of the aforementioned genes. Most importantly, constitutive overexpression of
dihydrodiol dehydrogenase (but not the other genes) in the 2008 cells led to induction of
cisplatin resistance, clearly indicating its role in the development of the resistance phenotype in the 2008/C13* cells. The development of
cisplatin resistance in the transfected cells was associated with an increase in the
dihydrodiol dehydrogenase enzyme activity. Although at present it is not clear how
dihydrodiol dehydrogenase is involved in
cisplatin resistance, the identification of this gene as a causal factor suggests the existence of a hitherto undefined pathway resulting in
cisplatin resistance.