1. Wnt inhibitor screen reveals iron dependence of β-catenin signaling in cancers.
- Author
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Song S, Christova T, Perusini S, Alizadeh S, Bao RY, Miller BW, Hurren R, Jitkova Y, Gronda M, Isaac M, Joseph B, Subramaniam R, Aman A, Chau A, Hogge DE, Weir SJ, Kasper J, Schimmer AD, Al-awar R, Wrana JL, and Attisano L
- Subjects
- Acute Disease, Administration, Oral, Benzoates pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Ciclopirox, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Deferasirox, Deferoxamine pharmacology, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, HEK293 Cells, Humans, Hydrazones chemistry, Iron Chelating Agents pharmacology, Leukemia, Myeloid drug therapy, Leukemia, Myeloid genetics, Leukemia, Myeloid pathology, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic genetics, Pyridones administration & dosage, Pyridones therapeutic use, Reverse Transcriptase Polymerase Chain Reaction, Triazoles pharmacology, Wnt Proteins genetics, Wnt Proteins metabolism, beta Catenin genetics, Hydrazones pharmacology, Iron metabolism, Wnt Proteins antagonists & inhibitors, Wnt Signaling Pathway drug effects, beta Catenin metabolism
- Abstract
Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/β-catenin signaling, we identified a series of acyl hydrazones that act downstream of the β-catenin destruction complex to inhibit both Wnt-induced and cancer-associated constitutive Wnt signaling via destabilization of β-catenin. We found that these acyl hydrazones bind iron in vitro and in intact cells and that chelating activity is required to abrogate Wnt signaling and block the growth of colorectal cancer cell lines with constitutive Wnt signaling. In addition, we found that multiple iron chelators, desferrioxamine, deferasirox, and ciclopirox olamine similarly blocked Wnt signaling and cell growth. Moreover, in patients with AML administered ciclopirox olamine, we observed decreased expression of the Wnt target gene AXIN2 in leukemic cells. The novel class of acyl hydrazones would thus be prime candidates for further development as chemotherapeutic agents. Taken together, our results reveal a critical requirement for iron in Wnt signaling and they show that iron chelation serves as an effective mechanism to inhibit Wnt signaling in humans.
- Published
- 2011
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