Iron-
sulfur (Fe-S)
proteins are thought to play an important role in
cancer cells mediating redox reactions, DNA replication, and telomere maintenance. Nutrient-deprivation autophagy factor-1 (NAF-1) is a 2Fe-2S
protein associated with the progression of multiple
cancer types. It is unique among Fe-S
proteins because of its 3Cys-1His cluster coordination structure that allows it to be relatively stable, as well as to transfer its clusters to apo-acceptor
proteins. Here, we report that overexpression of NAF-1 in xenograft
breast cancer tumors results in a dramatic augmentation in
tumor size and aggressiveness and that NAF-1 overexpression enhances the tolerance of
cancer cells to oxidative stress. Remarkably, overexpression of a NAF-1 mutant with a single point mutation that stabilizes the NAF-1 cluster, NAF-1(H114C), in xenograft
breast cancer tumors results in a dramatic decrease in
tumor size that is accompanied by enhanced mitochondrial
iron and reactive
oxygen accumulation and reduced cellular tolerance to oxidative stress. Furthermore, treating
breast cancer cells with
pioglitazone that stabilizes the 3Cys-1His cluster of NAF-1 results in a similar effect on mitochondrial
iron and
reactive oxygen species accumulation. Taken together, our findings point to a key role for the unique 3Cys-1His cluster of NAF-1 in promoting rapid
tumor growth through cellular resistance to oxidative stress. Cluster transfer reactions mediated by the overexpressed NAF-1
protein are therefore critical for inducing oxidative stress tolerance in
cancer cells, leading to rapid
tumor growth, and drugs that stabilize the NAF-1 cluster could be used as part of a treatment strategy for
cancers that display high NAF-1 expression.