Wnt Inhibitor Screen Reveals Iron Dependence of beta-Catenin Signaling in Cancers
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.
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ABSTRACT: Excess iron is tightly associated with tumorigenesis in multiple human cancer types through a variety of mechanisms including catalyzing the formation of mutagenic hydroxyl radicals, regulating DNA replication, repair and cell cycle progression, affecting signal transduction in cancer cells, and acting as an essential nutrient for proliferating tumor cells. Thus, multiple therapeutic strategies based on iron deprivation have been developed in cancer therapy. During the past few years, our understanding of genetic association and molecular mechanisms between iron and tumorigenesis has expanded enormously. In this review, we briefly summarize iron homeostasis in mammals, and discuss recent progresses in understanding the aberrant iron metabolism in numerous cancer types, with a focus on studies revealing altered signal transduction in cancer cells.Protein & Cell 12/2014; 6(2). DOI:10.1007/s13238-014-0119-z · 2.85 Impact Factor
- Leukemia Research 09/2014; 38(9). DOI:10.1016/j.leukres.2014.06.021 · 2.69 Impact Factor
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ABSTRACT: Iron plays a crucial role in a number of metabolic pathways including oxygen transport, DNA synthesis, and ATP generation. Although insufficient systemic iron can result in physical impairment, excess iron has also been implicated in a number of diseases including ischemic heart disease, diabetes, and cancer. Iron chelators are agents which bind iron and facilitate its excretion. Experimental iron chelators have demonstrated potent anti-neoplastic properties in a number of cancers in vitro. These agents have yet to be translated into clinical practice, however, largely due to the significant side effects encountered in pre-clinical models. A number of licenced chelators, however, are currently in clinical use for the treatment of iron overload associated with certain non-neoplastic diseases. Deferasirox is one such agent and the drug has shown significant anti-tumor effects in a number of in vitro and in vivo studies. Deferasirox is orally administered and has demonstrated a good side effect profile in clinical practice to date. It represents an attractive agent to take forward into clinical trials of iron chelators as anti-cancer agents.The Journal of Clinical Pharmacology 09/2013; 53(9). DOI:10.1002/jcph.113 · 2.47 Impact Factor