Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer (original) (raw)

Nature Chemical Biology volume 5, pages 100–107 (2009)Cite this article

Abstract

The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/β-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/β-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.

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Acknowledgements

We thank M. Bienz (Medical Research Council Laboratory of Molecular Biology), R.T. Moon (University of Washington), P.T. Chuang (University of California, San Francisco), J. Laborda (University of Castilla-La Mancha), G. Johnson (University of Alabama at Birmingham), P. Beachy (Stanford University), J. Minna, M. Brown and J. Goldstein (University of Texas Southwestern Medical Center) for reagents, and D. Frantz, K. Lillard, the University of Texas Southwestern Pathology Core, S. McKnight and the High-Throughput Screening Core for support with the chemical screen. This work was supported by the US National Cancer Institute (PO1 CA095471; Z.M., J.K. and N.S.W.), the US National Institute of General Medical Sciences (1R01GM076398-01), the American Cancer Society (RSG GMC-112251), the Welch Foundation (I-1665), a High Risk/High Impact award from the University of Texas Southwestern and an endowment from Virginia Murchison Linthicum.

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Author notes

  1. Baozhi Chen and Michael E Dodge: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA
    Baozhi Chen, Michael E Dodge, Wei Tang, Chih-Wei Fan & Lawrence Lum
  2. Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA
    Jianming Lu, Zhiqiang Ma, Shuguang Wei, Wayne Hao, Jessica Kilgore, Noelle S Williams, Michael G Roth & Chuo Chen
  3. Departments of Pediatrics, Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, Texas, USA
    James F Amatruda

Authors

  1. Baozhi Chen
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  2. Michael E Dodge
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  3. Wei Tang
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  4. Jianming Lu
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  5. Zhiqiang Ma
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  6. Chih-Wei Fan
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  7. Shuguang Wei
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  8. Wayne Hao
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  9. Jessica Kilgore
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  10. Noelle S Williams
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  11. Michael G Roth
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  12. James F Amatruda
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  13. Chuo Chen
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  14. Lawrence Lum
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Contributions

B.C., M.E.D., W.T., C.-W.F., S.W., W.H., J.K., N.S.W., M.G.R., J.F.A., C.C. and L.L. designed the experiments and analyzed the results. B.C., M.E.D., C.C. and L.L. wrote the manuscript. J.F.A. and B.C. performed zebrafish experiments. J.L., Z.M. and C.C. synthesized compounds.

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Correspondence toLawrence Lum.

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The authors declare competing financial interests in the form of a pending patent application.

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Chen, B., Dodge, M., Tang, W. et al. Small molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.Nat Chem Biol 5, 100–107 (2009). https://doi.org/10.1038/nchembio.137

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