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Nitric Oxide: Genomic Instability And Synthetic Lethality.
1Massey Cancer Center, Virginia Commonwealth University, Richmond, USA.
Redox Biology
|February 7, 2017
Summary
Inflammation-induced nitric oxide (NO) impairs DNA repair by downregulating BRCA1 and increasing miRNA-155, leading to genomic instability. Combining NO donors with PARP inhibitors sensitizes BRCA1-positive cancer cells to DNA damage.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Inflammatory conditions promote carcinogenesis via inducible nitric oxide synthase (iNOS) and nitric oxide/reactive nitrogen species (NO/RNS).
- NO/RNS contribute to genomic instability by inhibiting Breast Cancer type 1 Susceptibility protein (BRCA1) expression, shifting DNA repair from homologous recombination repair (HRR) to nonhomologous end joining (NHEJ).
- BRCA1 epigenetically suppresses miRNA-155, which targets mismatch repair (MMR) core proteins (MSH2, MSH6, MLH1), leading to microsatellite instability (MSI).
Purpose of the Study:
- To elucidate the NO-dependent mechanisms contributing to genomic instability in carcinogenesis.
- To investigate the role of the BRCA1/miRNA-155 pathway in NO-induced downregulation of MMR proteins and MSI.
- To evaluate the therapeutic potential of combining NO donors with PARP inhibitors in BRCA1-positive cancer cells.
Main Methods:
- Investigated NO/RNS effects on BRCA1 expression and DNA repair pathways (HRR, NHEJ).
- Assessed the epigenetic regulation of miRNA-155 by BRCA1 and its impact on MMR proteins (MSH2, MSH6, MLH1).
- Utilized NO donors and Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors in BRCA1-positive and deficient cancer cell models.
Main Results:
- Demonstrated NO-dependent downregulation of BRCA1 and subsequent upregulation of miRNA-155, leading to MSI.
- Confirmed NO-dependent reduction of MMR core proteins (MSH2, MSH6, MLH1) via the ↓BRCA1/↑miRNA-155 pathway.
- Showed that combined NO donors and PARP inhibitors significantly sensitized BRCA1-positive cancer cells to DNA-damaging agents.
Conclusions:
- NO/RNS-induced genomic instability is mediated by BRCA1 inhibition and MMR deficiency.
- The BRCA1/miRNA-155 axis is a critical NO-sensitive pathway driving MSI.
- Combination therapy with NO donors and PARP inhibitors represents a promising strategy for treating BRCA1-positive cancers.
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