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Published on: June 17, 2014
Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway
1Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA. delu@ucsd.edu
Background:
Wnt signaling affects fundamental development pathways by regulating cell proliferation and differentiation. Aberrant activation of Wnt/beta-catenin signaling promotes the development of several cancers and is an attractive target for chemopreventive and chemotherapeutic agents.
Results:
In order to identify the novel antagonists for the Wnt/beta-catenin pathway, we employed a cell-based Wnt reporter system (TOPflash) to screen a library of 960 known drugs. We identified spiperone, a psychotropic drug, as a novel Wnt inhibitor, which specifically blocks canonical Wnt signaling prior to the activation of beta-catenin. The Wnt inhibitory function of spiperone is not associated with its dopamine-, serotonin- and sigma-receptor antagonist properties. Instead, spiperone increases intracellular calcium levels in a similar manner to thapsigargin, that also impedes Wnt signal transduction. Inhibition of protein kinase C had no effect on spiperone-mediated antagonism of Wnt signaling.
Conclusion:
Spiperone is a calcium regulator. It inhibits Wnt signaling by enhancing intracellular calcium levels.
Insights
Spiperone, a psychotropic drug, was identified as a novel Wnt signaling inhibitor. It functions by increasing intracellular calcium levels, offering potential for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Wnt signaling is crucial for cell development, regulating proliferation and differentiation.
- Aberrant Wnt/beta-catenin signaling drives cancer development, making it a therapeutic target.
Purpose of the Study:
- To identify novel antagonists of the Wnt/beta-catenin pathway.
- To explore potential chemopreventive and chemotherapeutic agents.
Main Methods:
- A cell-based Wnt reporter system (TOPflash) was used for drug screening.
- A library of 960 known drugs was screened.
- Spiperone's mechanism of action was investigated, including its effects on receptor antagonism and intracellular calcium levels.
Main Results:
- Spiperone was identified as a novel Wnt signaling inhibitor.
- It specifically blocks canonical Wnt signaling before beta-catenin activation.
- Spiperone increases intracellular calcium levels, similar to thapsigargin, which also inhibits Wnt signaling.
- Its inhibitory effect is independent of dopamine, serotonin, and sigma-receptor antagonism.
Conclusions:
- Spiperone acts as a calcium regulator.
- It inhibits Wnt signaling by elevating intracellular calcium levels.
- This suggests spiperone's potential as a Wnt pathway antagonist for cancer treatment.
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