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

Loss of p53 gene function, which occurs in most colon cancer cells, has bee n shown to abolish the apoptotic response to 5-fluorouracil (54U). To ident ify genes downstream of p53 that might mediate these effects, we assessed g lobal patterns of gene expression following 5-FU treatment of isogenic cell s differing only in their p53 status. The gene encoding mitochondrial ferre doxin reductase (protein, FR; gene, FDXR) was one of the few genes signific antly induced by p53 after 5-FU treatment. The FR protein was localized to mitochondria and suppressed the growth of colon cancer cells when over-expr essed. Targeted disruption of the FDXR gene in human colon cancer cells sho wed that it was essential for viability, and partial disruption of the gene resulted in decreased sensitivity to 5-FU-induced apoptosis. These data, c oupled with the effects of pharmacologic inhibitors of reactive oxygen spec ies, indicate that FIR contributes to p53-mediated apoptosis through the ge neration of oxidative stress in mitochondria.