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.
Highlights
Prostate cancer is the second most common cancer among men, with 206,640 men diagnosed and 28,088 dying from prostate cancer in 2012 [1]
Genome-wide analysis of gene expression in DU-145 human prostate cancer cells revealed downregulation of promising antitumor targets by the novel quinazoline derivative DZ-50, including Epithelial-mesenchymal transition (EMT)-associated genes, angiogenesis associated genes (TSP-1), genes associated with intercellular tight junctions (TJ) as well as serine threonine kinase 31 (TSK31) and insulin growth factor binding protein 3 (IGFBP-3)
Recent evidence suggested that talin confers anoikis resistance in prostate cancer cells towards metastases, via its ability to stabilize focal adhesions and propagate focal adhesion complex signaling through the Akt survival signaling [10]
Summary
Prostate cancer is the second most common cancer among men, with 206,640 men diagnosed and 28,088 dying from prostate cancer in 2012 [1]. Focal adhesions are vital for both normal contact-dependent signaling by normal cells and invasion, migration and metastasis of malignant cells. Work from this laboratory identified new anti-tumor action exerted by drugs classically used for the treatment of benign prostatic hyperplasia (quinazoline-a1-adrenoceptor antagonists) via induction of the extrinsic apoptosis cascade (death receptor activation, caspase-8 cleavage and inhibition of AKT survival signaling) [3,4,5]. Anoikis resistance is closely linked to increased metastatic potential in many human malignancies, including prostate cancer [10], renal cell carcinoma [11], breast cancer [12] as well as tumors of mesenchymal origin [13]
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