Abstract
Cancer cell resistance to anoikis driven by aberrant signaling sustained by the tumor microenvironment confers high invasive potential and therapeutic resistance. We recently generated a novel lead quinazoline-based Doxazosin® derivative, DZ-50, which impairs tumor growth and metastasis via anoikis. Genome-wide analysis in the human prostate cancer cell line DU-145 identified primary downregulated targets of DZ-50, including genes involved in focal adhesion integrity (fibronectin, integrin-α6 and talin), tight junction formation (claudin-11) as well as insulin growth factor binding protein 3 (IGFBP-3) and the angiogenesis modulator thrombospondin 1 (TSP-1). Confocal microscopy demonstrated structural disruption of both focal adhesions and tight junctions by the downregulation of these gene targets, resulting in decreased cell survival, migration and adhesion to extracellular matrix (ECM) components in two androgen-independent human prostate cancer cell lines, PC-3 and DU-145. Stabilization of cell-ECM interactions by overexpression of talin-1 and/or exposing cells to a fibronectin-rich environment mitigated the effect of DZ-50. Loss of expression of the intracellular focal adhesion signaling effectors talin-1 and integrin linked kinase (ILK) sensitized human prostate cancer to anoikis. Our findings suggest that DZ-50 exerts its antitumor effect by targeting the key functional intercellular interactions, focal adhesions and tight junctions, supporting the therapeutic significance of this agent for the treatment of advanced prostate cancer.
Document Type
Article
Publication Date
1-31-2014
Digital Object Identifier (DOI)
http://dx.doi.org/10.1371/journal.pone.0086238
Repository Citation
Hensley, Patrick J.; Desiniotis, Andreas; Wang, Chi; Stromberg, Arnold J.; Chen, Ching-Shih; and Kyprianou, Natasha, "Novel Pharmacologic Targeting of Tight Junctions and Focal Adhesions in Prostate Cancer Cells" (2014). Surgery Faculty Publications. 10.
https://uknowledge.uky.edu/surgery_facpub/10
Notes/Citation Information
Published in PLoS ONE, v. 9, issue 1, no. e86238.
© 2014 Hensley et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.