Novel pharmacologic targeting of tight junctions and focal adhesions in prostate cancer cells.
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.
Department of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America ; Department of Pathology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
Patrick J
PJ
Hensley
Department of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
Andreas
A
Desiniotis
Department of Biostatistics, University of Kentucky College of Public Health, Lexington, Kentucky, United States of America.
Chi
C
Wang
Department of Statistics, University of Kentucky, Lexington, Kentucky, United States of America.
Arnold
A
Stromberg
Division of Medicinal Chemistry, Ohio State University College of Pharmacy, Columbus, Ohio, United States of America.
Ching-Shih
CS
Chen
Department of Urology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America ; Department of Pathology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America ; Department of Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America ; Department of Molecular & Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
Natasha
N
Kyprianou
D023102:Anoikis / Q000187:drug effects / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D017292:Doxazosin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D039503:Integrin alpha6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016608:Talin / Q000235:genetics / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D000099200:Scaffold Protein ILK
D057167:Claudins; D017292:Doxazosin; D005353:Fibronectins; D018972:Insulin-Like Growth Factor Binding Protein 3; D039503:Integrin alpha6; D017346:Protein Serine-Threonine Kinases; D016608:Talin; D019700:Thrombospondin 1; D000099200:Scaffold Protein ILK; C525921:2-(4-(biphenyl-4-sulfonyl)-piperazin-1-yl)-6,7-dipropoxyquinazolin-4-yl-amine; C120453:CLDN11 protein, human