Iron is essential for proliferation of normal and neoplastic cells. Cellular
iron uptake, utilization and storage are regulated by transcriptional and post-transcriptional mechanisms. We hypothesized that the disruption of
iron homeostasis may modulate the growth properties of
cancer cells. To address this, we employed H1299
lung cancer cells engineered for
tetracycline-inducible overexpression of the post-transcriptional regulator
iron regulatory protein 1 (IRP1). The induction of IRP1 (wild-type or the constitutive IRP1(C437S) mutant) did not affect the proliferation of the cells in culture, and only modestly reduced their efficiency to form colonies in soft
agar. However, IRP1 dramatically impaired the capacity of the cells to form solid
tumor xenografts in nude mice.
Tumors derived from IRP1-transfectants were <20% in size compared to those from parent cells. IRP1 coordinately controls the expression of
transferrin receptor 1 (TfR1) and
ferritin by binding to
iron-responsive elements (IREs) within their mRNAs. Biochemical analysis revealed high expression of
epitope-tagged IRP1 in
tumor tissue, which was associated with a profound increase in IRE-binding activity. As expected, this response misregulated
iron metabolism by increasing TfR1 levels. Surprisingly, IRP1 failed to suppress
ferritin expression and did not affect the levels of the
iron transporter
ferroportin. Our results show that the overexpression of IRP1 is associated with an apparent
tumor suppressor phenotype and provide a direct regulatory link between the IRE/IRP system and
cancer.