The Effects of Iron Levels on the Interaction between Polyamine Metabolism and Iron Metabolism in Neoplastic Cells

Abstract

Iron is a crucial element that is associated with many metabolic pathways important for life sustaining processes. Polyamines are small positively charged polycations involved in various physiological functions. Both iron and polyamines levels are known to be high in cancer cells which suggests a possible unexplored link between the two metabolic pathways. For the first time, we demonstrate that iron-depletion robustly regulates the expression of 13 polyamine pathway proteins. Iron-depletion also decreased polyamine and S-adenosylmethionine levels (required for spermidine/spermine biosynthesis) and decreased 3H-spermidine uptake in accordance with expression of the polyamine importer, SLC22A16. The “reprogramming” of polyamine metabolism by iron-depletion showed dependence on the proto-oncogene, c-Myc, and tumour suppressor, p53 expression. Furthermore, the ability of iron chelators to inhibit proliferation can be rescued by polyamine supplementation. Collectively, these data demonstrate that iron and polyamine metabolism are closely linked at multiple levels. Moreover, we have identified that the mRNA and protein expression of the iron-containing enzyme, aci-reductone dioxygenase 1 (ADI1), was regulated by iron levels. Cellular iron depletion or deficient ADI1 metalation by the iron chaperone, PCBP1, promotes the proteasomal degradation of ADI1. Collectively, this demonstrates that cellular iron regulates ADI1 stability, a key enzyme involved in methionine salvage, polyamine biosynthesis and proliferation. In addition to regulating ADI1, poly(rC)-binding proteins (PCBPs) have been reported to function as iron-binding chaperones that deliver iron to ferritin. We observed that PCBP2 enhances, while PCBP1 inhibits ferritin 59Fe-loading and ferritin protein expression. Our results suggest that the regulation of ferritin iron-loading by PCBPs may involve a combination of translational regulation and/or iron chaperone activity. Overall this study has demonstrated for the first time the direct interaction between iron metabolism and polyamine metabolism, which is important in understanding how cancer cells can survive adverse environments.