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

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.

• Authors: P M Hwang, F Bunz, J Yu, C Rago, T A Chan, M P Murphy, G F Kelso, R A Smith, K W Kinzler, B Vogelstein
• Journal: Nature medicine (Nat Med) Vol. 7 Issue 10 Pg. 1111-7 (Oct 2001) ISSN: 1078-8956 [Print] United States
• PMID: 11590433 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimetabolites, Antineoplastic
• Tumor Suppressor Protein p53
• Ferredoxin-NADP Reductase
• Fluorouracil

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis
• Cell Division (drug effects)
• Colorectal Neoplasms
• Ferredoxin-NADP Reductase (genetics, physiology)
• Flow Cytometry
• Fluorouracil (pharmacology)
• Gene Expression (drug effects)
• Gene Targeting (methods)
• Humans
• Oxidative Stress
• Recombination, Genetic
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, metabolism)