Spiperone enhances intracellular calcium level and inhibits the Wnt signaling pathway.
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.


CONCLUSIONS
Spiperone is a calcium regulator. It inhibits Wnt signaling by enhancing intracellular calcium levels.
Lu
Desheng
D
Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA. delu@ucsd.edu
Carson
Dennis A
DA
D002118:Calcium / Q000819:agonists / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D013134:Spiperone / Q000494:pharmacology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D051153:Wnt Proteins; D013134:Spiperone; D002118:Calcium