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Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells
1Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract:
Loss of p53 gene function, which occurs in most colon cancer cells, has been shown to abolish the apoptotic response to 5-fluorouracil (5-FU). To identify genes downstream of p53 that might mediate these effects, we assessed global patterns of gene expression following 5-FU treatment of isogenic cells differing only in their p53 status. The gene encoding mitochondrial ferredoxin reductase (protein, FR; gene, FDXR) was one of the few genes significantly induced by p53 after 5-FU treatment. The FR protein was localized to mitochondria and suppressed the growth of colon cancer cells when over-expressed. Targeted disruption of the FDXR gene in human colon cancer cells showed that it was essential for viability, and partial disruption of the gene resulted in decreased sensitivity to 5-FU-induced apoptosis. These data, coupled with the effects of pharmacologic inhibitors of reactive oxygen species, indicate that FR contributes to p53-mediated apoptosis through the generation of oxidative stress in mitochondria.
Insights
The p53 tumor suppressor gene is crucial for colon cancer cell death after 5-fluorouracil (5-FU) treatment. Mitochondrial ferredoxin reductase (FDXR) mediates this p53-dependent apoptosis via oxidative stress.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Loss of p53 gene function is common in colon cancer, leading to resistance to 5-fluorouracil (5-FU) chemotherapy.
- Understanding p53-regulated genes is vital for overcoming 5-FU resistance in colon cancer.
Purpose of the Study:
- To identify genes regulated by p53 that mediate apoptosis in response to 5-FU.
- To investigate the role of mitochondrial ferredoxin reductase (FDXR) in p53-dependent apoptosis.
Main Methods:
- Global gene expression profiling of isogenic colon cancer cells with and without p53 function after 5-FU treatment.
- Overexpression and gene disruption of FDXR in human colon cancer cells.
- Assessment of cell viability, apoptosis, and reactive oxygen species generation.
Main Results:
- FDXR was identified as a key gene induced by p53 following 5-FU treatment.
- Overexpression of FR suppressed colon cancer cell growth, while FDXR disruption impaired viability.
- Partial FDXR disruption reduced sensitivity to 5-FU-induced apoptosis, implicating FR in this process.
- FDXR contributes to p53-mediated apoptosis through mitochondrial oxidative stress.
Conclusions:
- FDXR is a critical mediator of p53-dependent apoptosis in colon cancer cells treated with 5-FU.
- Targeting FDXR or modulating mitochondrial oxidative stress may represent novel therapeutic strategies for 5-FU-resistant colon cancer.
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