Wnt Inhibitor Screen Reveals Iron Dependence of -Catenin Signaling in Cancers

Department of Biochemistry, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
Cancer Research (Impact Factor: 9.33). 12/2011; 71(24):7628-39. DOI: 10.1158/0008-5472.CAN-11-2745
Source: PubMed


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.

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Available from: Tania Christova, Jan 03, 2016
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    • "This effect may partly be related to the dependency of the aberrantly activated, tumor-promoting Wnt/␤-catenin pathway on iron excess. On the other hand, Wnt/␤-catenin signaling has been shown to be required for the development of a highly proliferative leukemic stem cell, necessary to maintain leukemias and high levels of ␤-catenin expression correlate with poor prognosis in AML [3]. Hence, the iron chelator DFO might inhibit the leukemic cell proliferation, not only through the reduction of the iron overload along with the decreased expression of NF-␬Bp65 and survivin and increased expression of the apoptotic proteins Bax and Caspase-3, as reported by Yu et al., but also through the abrogation of Wnt/␤catenin signaling. "

    Full-text · Article · Sep 2014 · Leukemia Research
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    • "Iron is an essential element involved in multiple key processes including DNA and heme synthesis, Wnt signalling, and cellular metabolism [4,5]. Many cancer cells exhibit an increased demand for iron in order to maintain their high cellular turnover and DNA synthesis. "
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