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

• Published in: Nature medicine Vol. 7; no. 10; pp. 1111 - 1117
• Main Authors: Vogelstein, Bert, Hwang, Paul M, Bunz, Fred, Yu, Jian, Rago, Carlo, Chan, Timothy A, Murphy, Michael P, Kelso, Geoffry F, Smith, Robin A. J, Kinzler, Kenneth W
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.10.2001
• Subjects: Antimetabolites, Antineoplastic - pharmacology; Apoptosis; Cell Division - drug effects; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms; ferredoxin reductase; Ferredoxin-NADP Reductase - genetics; Ferredoxin-NADP Reductase - physiology; Flow Cytometry; Fluorouracil - pharmacology; Gene expression; Gene Expression - drug effects; Gene Targeting - methods; Humans; Inhibitors; Medicine; Mitochondria; Oxidative Stress; Phosphatase; Proteins; Publishing; Recombination, Genetic; Tumor Cells, Cultured; Tumor necrosis factor-TNF; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; United States > US; Maryland
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1001-1111

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.