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

TitleFerredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells.
Publication TypeJournal Article
Year of Publication2001
AuthorsHwang, PM, Bunz, F, Yu, J, Rago, C, Chan, TA, Murphy, MP, Kelso, GF, Smith, RA, Kinzler, KW, Vogelstein, B
JournalNat Med
Volume7
Issue10
Pagination1111-7
Date Published2001 Oct
ISSN1078-8956
KeywordsAntimetabolites, Antineoplastic, Apoptosis, Cell Division, Colorectal Neoplasms, Ferredoxin-NADP Reductase, Flow Cytometry, Fluorouracil, Gene Expression, Gene Targeting, Humans, Oxidative Stress, Recombination, Genetic, Tumor Cells, Cultured, Tumor Suppressor Protein p53
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.

DOI10.1038/nm1001-1111
Alternate JournalNat. Med.
Citation Key10.1038/nm1001-1111
PubMed ID11590433
PubMed Central IDPMC4086305
Grant ListR37 CA043460 / CA / NCI NIH HHS / United States
T32 GM007184 / GM / NIGMS NIH HHS / United States
CA 43460 / CA / NCI NIH HHS / United States
GM 07184 / GM / NIGMS NIH HHS / United States