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Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.

Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, Wei S, Hao W, Kilgore J, Williams NS, Roth MG, Amatruda JF, Chen C, Lum L - Nat. Chem. Biol. (2009)

Bottom Line: 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/beta-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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

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/beta-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/beta-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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Related in: MedlinePlus

The effects of IWR-1 on caudal fin regeneration are reversibleAdult zebrafish with resected caudal fins were placed in water containing DMSO carrier or IWR-1 (10μM) for 7 days with replenishment of breeding water and compounds every day. Consistent with inhibition of Wnt/β-catenin pathway response by IWR-1, fish treated with IWR-1 but not DMSO failed to regenerate fin tissue. Nine days post-removal of chemicals, fish that were treated with IWR-1 display tissue regrowth suggesting the pluripotent cells required for regeneration are able to resume normal function. Numbers designate specific animals. Four fish were analyzed in each group. Scale bar: 2.5mm.
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Figure 6: The effects of IWR-1 on caudal fin regeneration are reversibleAdult zebrafish with resected caudal fins were placed in water containing DMSO carrier or IWR-1 (10μM) for 7 days with replenishment of breeding water and compounds every day. Consistent with inhibition of Wnt/β-catenin pathway response by IWR-1, fish treated with IWR-1 but not DMSO failed to regenerate fin tissue. Nine days post-removal of chemicals, fish that were treated with IWR-1 display tissue regrowth suggesting the pluripotent cells required for regeneration are able to resume normal function. Numbers designate specific animals. Four fish were analyzed in each group. Scale bar: 2.5mm.

Mentions: Achieving transient repression of pathological Wnt response without incurring permanent damage to normal stem cell function is a key anti-cancer therapeutic goal. We tested for the ability of zebrafish to resume regenerative processes following a chemically induced blockade of fin re-growth. Fish with resected caudal fins that were breed in water containing IWR-1 for 7 days were able to regenerate tissue to nearly normal levels subsequent to chemical removal, suggesting that transient inhibition of Wnt/β-catenin response did not permanently alter the ability of stem cells to self-renew (Fig. 6).


Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.

Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW, Wei S, Hao W, Kilgore J, Williams NS, Roth MG, Amatruda JF, Chen C, Lum L - Nat. Chem. Biol. (2009)

The effects of IWR-1 on caudal fin regeneration are reversibleAdult zebrafish with resected caudal fins were placed in water containing DMSO carrier or IWR-1 (10μM) for 7 days with replenishment of breeding water and compounds every day. Consistent with inhibition of Wnt/β-catenin pathway response by IWR-1, fish treated with IWR-1 but not DMSO failed to regenerate fin tissue. Nine days post-removal of chemicals, fish that were treated with IWR-1 display tissue regrowth suggesting the pluripotent cells required for regeneration are able to resume normal function. Numbers designate specific animals. Four fish were analyzed in each group. Scale bar: 2.5mm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2628455&req=5

Figure 6: The effects of IWR-1 on caudal fin regeneration are reversibleAdult zebrafish with resected caudal fins were placed in water containing DMSO carrier or IWR-1 (10μM) for 7 days with replenishment of breeding water and compounds every day. Consistent with inhibition of Wnt/β-catenin pathway response by IWR-1, fish treated with IWR-1 but not DMSO failed to regenerate fin tissue. Nine days post-removal of chemicals, fish that were treated with IWR-1 display tissue regrowth suggesting the pluripotent cells required for regeneration are able to resume normal function. Numbers designate specific animals. Four fish were analyzed in each group. Scale bar: 2.5mm.
Mentions: Achieving transient repression of pathological Wnt response without incurring permanent damage to normal stem cell function is a key anti-cancer therapeutic goal. We tested for the ability of zebrafish to resume regenerative processes following a chemically induced blockade of fin re-growth. Fish with resected caudal fins that were breed in water containing IWR-1 for 7 days were able to regenerate tissue to nearly normal levels subsequent to chemical removal, suggesting that transient inhibition of Wnt/β-catenin response did not permanently alter the ability of stem cells to self-renew (Fig. 6).

Bottom Line: 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/beta-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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.

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/beta-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/beta-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.

Show MeSH
Related in: MedlinePlus