Influence of the proto-oncogene c-fos cisplatin sensitivity

Cisplatin resistance has been associated with overexpression of the c-fos g ene in a human ovarian carcinoma cell line. To determine whether the correl ation between c-fos overexpression and cisplatin resistance was limited to this cell line or was a more generalized phenomenon, we investigated cispla tin sensitivity in rat fibroblast cells that overexpressed the c-fos gene. The cisplatin IC50 values for two different c-fos transfectants, CMVc-fos a nd L1-3c-fos, were 7.6 +/- 0.8 and 5.6 +/- 1.0 mu M, respectively, whereas the cisplatin IC50 value for the parental line, 208F, was 2.4 +/- 0.1 mu M This represented a 3.2- and 2.3-fold resistance to cisplatin for CMVc-fos a nd L1-3c-fos cells, respectively. The correlation between c-fos expression and cisplatin resistance also was examined in a human ovarian carcinoma cel l lint, 2008, and its cisplatin-resistant variant, C13* Expression of c-fos was elevated slightly at both the mRNA and protein levels in the C13* cell s compared with 2008 cells, and c-Fos protein levels were induced in C13* c ells following cisplatin treatment. In addition, it was observed that C13*; cells were significantly more sensitive than 2008 cells to a c-fos antisen se oligonucleotide. The re,, values for the c-fos antisense oligonucleotide were 19.9 +/- 5.0 pmol for C13*: cells and 58.1 +/- 6.0 pmol for 2008 cell s (P = 0.0012). Furthermore, combinations of c-fos antisense and cisplatin reduced the amount of cisplatin required to kill 50% of the C13* cells, alt hough the interaction was not synergistic. These results suggest that expre ssion of the c-Jos gene can influence cisplatin sensitivity, and that c-fos antisense oligonucleotide based therapy may be effective at killing parent al and cisplatin-resistant. ovarian carcinoma cells, either alone or in com bination with cisplatin. BIOCHEM PHARMACOL 59;4:337-345, 2000. (C) 2000 Els evier Science Inc.