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Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
IRF-1 expression is induced by cisplatin in ovarian cancer cells and limits drug effectiveness
Simona Pavan1, Martina Olivero, Davide Corà
1Department of Oncological Sciences, University of Torino School of Medicine, Turin, Italy.
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.
Insights
Interferon Regulatory Factor-1 (IRF-1) is upregulated by cisplatin in ovarian cancer cells. While IRF-1 may limit treatment response by inhibiting proliferation, its silencing sensitizes cells to cisplatin-induced apoptosis.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Interferon Regulatory Factors (IRFs) are key transcription factors in immune responses and oncogenesis, often acting as tumor suppressors.
- IRF expression and activation are triggered by cytokines and DNA damage.
- This study investigates the role of IRF-1 in ovarian cancer cell response to cisplatin (CDDP).
Purpose of the Study:
- To elucidate the function of IRF-1 in ovarian cancer cells treated with cisplatin.
- To determine how IRF-1 influences cellular responses like proliferation, apoptosis, and cell cycle progression.
Main Methods:
- Transcriptional profiling of ovarian cancer cells using expression microarrays after CDDP treatment and IRF-1 silencing.
- Functional assays including cell cycle analysis, colony formation, and apoptosis assessment following IRF-1 manipulation (silencing and overexpression).
Main Results:
- CDDP treatment increased IRF-1 expression and nuclear translocation in ovarian cancer cells, altering target gene expression.
- IRF-1 overexpression suppressed the transformed phenotype and induced G1 arrest and p21 expression.
- IRF-1 silencing sensitized cells to CDDP-induced apoptosis and reduced p21 induction.
Conclusions:
- IRF-1 is upregulated by CDDP in ovarian cancer cells and may limit therapeutic efficacy by inhibiting proliferation.
- IRF-1 induction could potentially antagonize the effectiveness of combination therapies involving platinum drugs and cytokines.
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