Work

Faculty Opinions recommendation of Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells.

Year: 2001

Type: peer-review

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.5-fluorouracil (5-FU) has been in clinical use for several decades and is still the most effective adjuvant therapy for patients with colon cancer.Metabolically, it acts by blocking the enzyme thymidylate synthase and by inhibiting both RNA and DNA synthesis.Like most chemotherapeutic agents, 5-FU induces marked apoptosis in sensitive cells.However, the molecular mechanisms underlying this apoptosis are only beginning to be elucidated.Several studies have suggested a correlation between inactivation of p53 and resistance to 5-FU, both in patients and in experimental systems 1,2 .For example, a profound resistance to 5-FU-induced apoptosis was observed in a human colon cancer cell line with a targeted disruption of the p53 gene (Trp53) 3 .Such observations support a genetic basis for 5-FU chemosensitivity and indicate that isogenic cells differing only in p53 status represent a useful system for studying chemosensitivity in vitro.

Source: Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

DOI: 10.3410/f.1001294.16758

Author: Scott Lowe

Institution: Cold Spring Harbor Laboratory

Language: English

Topic: Cancer-related Molecular Pathways

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Johns Hopkins University, National Institutes of Health