IRF-1 expression is induced by cisplatin in ovarian cancer cells and limits drug effectiveness.

BACKGROUND

The Interferon Regulatory Factors (IRFs) are transcription factors involved in immune responses and oncogenesis and most of them are classified as tumour suppressors. The expression and activation of IRF(s) are stimulated by several cytokines and by DNA damage. Here we examine the role of the IRF-1 in the response of ovarian cancer cells to the front-line chemotherapeutic drug cisplatin (CDDP).

METHODS

We evaluated the transcriptional response of three ovarian cancer cell lines to CDDP both under control conditions and after IRF-1 silencing using expression microarrays. The role played by IRF-1 in the response of these cells to CDDP was evaluated after silencing and overexpressing IRF-1. We studied cell cycle progression, colony forming ability in monolayer culture and semisolid medium, and apoptosis in the response to the drug.

RESULTS

The treatment of ovarian cancer cells with CDDP boosted the expression and the nuclear translocation of IRF-1, which in turn modulated the expression of putative IRF-1 target genes. Accordingly, IRF-1 silencing re-orchestrated the expression profiles of CDDP-treated cells. In agreement with its role as a tumour suppressor, overexpressing IRF-1 suppressed the transformed phenotype of ovarian cancer cells. Nevertheless, IRF-1 silencing sensitized cells to the apoptotic death induced by CDDP. Over-expression was associated with cell G1 arrest and p21 induction irrespective of p53 proficiency, while IRF-1 silencing reduced the induction of p21 by CDDP.

CONCLUSIONS

These data demonstrate that IRF-1 is up-regulated by CDDP in ovarian cancer cells and might limit the cell response to CDDP, likely by inhibiting cell proliferation. Data suggest that IRF-1 induction might interfere with the effectiveness of combination therapy with platinum drugs and cytokines.