Abstract
Because cancer cell invasion is a critical determinant of metastasis, targeting invasion is a viable approach to prevent metastasis. Utilizing a novel three-dimensional high-throughput invasion assay, we screened a National Cancer Institute compound library and discovered compounds demonstrating inhibitory effects on cancer cell invasion. One hit, trifluoperazine, suppresses invasion of human cancer cell lines while displaying a limited cytotoxicity profile. This inhibition is due to the interference with cancer cell migratory ability but not proteolytic activity. Treatment of cancer cells with trifluoperazine significantly reduces angiogenesis and prevents cancer cell invasion through a chorioallantoic basement membrane. Mechanistically, treatment results in decreased phosphorylated AKT (Ser473 and Thr308) and β-catenin (Ser552). Lack of phosphorylation of Ser552 of β-catenin prevents β-catenin nuclear relocation, resulting in decreased expression of vascular endothelial growth factor, likely mediated through dopamine receptor D2. Taken together, we demonstrated that trifluoperazine is responsible for reducing the angiogenic and invasive potential of aggressive cancer cells through dopamine receptor D2 to modulate the β-catenin pathway and propose that trifluoperazine may be used as an antimetastasis chemotherapeutic.
Footnotes
- Received November 18, 2014.
- Accepted December 31, 2014.
This work was supported in part by the Baldwin Breast Cancer Foundation and National Cancer Institute [1R01CA166936 to J.C.] and the United States Army Medical Research Acquisition Activity award [W81XWH10-1-0873 to B.R.].
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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