Wnt inhibitor screen reveals iron dependence of β-catenin signaling in cancers.
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.
Department of Biochemistry, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
Siyuan
S
Song
Tania
T
Christova
Stephen
S
Perusini
Solmaz
S
Alizadeh
Ren-Yue
RY
Bao
Bryan W
BW
Miller
Rose
R
Hurren
Yulia
Y
Jitkova
Marcela
M
Gronda
Methvin
M
Isaac
Babu
B
Joseph
Ratheesh
R
Subramaniam
Ahmed
A
Aman
Anh
A
Chau
Donna E
DE
Hogge
Scott J
SJ
Weir
James
J
Kasper
Aaron D
AD
Schimmer
Rima
R
Al-awar
Jeff L
JL
Wrana
Liliana
L
Attisano
D000208:Acute Disease; D000284:Administration, Oral; D001565:Benzoates / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077768:Ciclopirox; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077588:Deferasirox; D003676:Deferoxamine / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D001565:Benzoates; D006835:Hydrazones; D007502:Iron Chelating Agents; D011728:Pyridones; D014230:Triazoles; D051153:Wnt Proteins; D051176:beta Catenin; D000077768:Ciclopirox; D007501:Iron; D003676:Deferoxamine; D000077588:Deferasirox