Influence of the proto-oncogene c-fos on cisplatin sensitivity

Cisplatin resistance has been associated with overexpression of the c-fos gene in a human ovarian carcinoma cell line. To determine whether the correlation between c-fos overexpression and cisplatin resistance was limited to this cell line or was a more generalized phenomenon, we investigated cisplatin sensitivity in rat fibroblast cells that overexpressed the c-fos gene. The cisplatin Ic50 values for two different c-fos transfectants, CMVc-fos and L1-3c-fos, were 7.6 +/- 0.8 and 5.6 +/- 1.0 microM, respectively, whereas the cisplatin Ic50 value for the parental line, 208F, was 2.4 +/- 0.1 microM. This represented a 3.2- and 2.3-fold resistance to cisplatin for CMVc-fos and L1-3c-fos cells, respectively. The correlation between c-fos expression and cisplatin resistance also was examined in a human ovarian carcinoma cell line, 2008, and its cisplatin-resistant variant, C13*. Expression of c-fos was elevated slightly at both the mRNA and protein levels in the C13* cells compared with 2008 cells, and c-Fos protein levels were induced in C13* cells following cisplatin treatment. In addition, it was observed that C13* cells were significantly more sensitive than 2008 cells to a c-fos antisense oligonucleotide. The Ic50 values for the c-fos antisense oligonucleotide were 19.9 +/- 5.0 pmol for C13* cells and 58.1 +/- 6.0 pmol for 2008 cells (P = 0.0012). Furthermore, combinations of c-fos antisense and cisplatin reduced the amount of cisplatin required to kill 50% of the C13* cells, although the interaction was not synergistic. These results suggest that expression of the c-fos gene can influence cisplatin sensitivity, and that c-fos antisense oligonucleotide based therapy may be effective at killing parental and cisplatin-resistant ovarian carcinoma cells, either alone or in combination with cisplatin.