Abstract
To study the role of FAK signaling complexes in promoting metastatic properties of prostate cancer (PCa) cells, we selected stable, highly migratory variants, termed PC3 Mig-3 and DU145 Mig-3, from two well-characterized PCa cell lines, PC3 and DU145. These variants were not only increased migration and invasion in vitro, but were also more metastatic to lymph nodes following intraprostatic injection into nude mice. Both PC3 Mig-3 and DU145 Mig-3 were specifically increased in phosphorylation of FAK Y861. We therefore examined potential alterations in Src family kinases responsible for FAK phosphorylation and determined only Yes expression was increased. Overexpression of Yes in PC3 parental cells and src-/-fyn-/-yes-/- fibroblasts selectively increased FAK Y861 phosphorylation, and increased migration. Knockdown of Yes in PC3 Mig-3 cells decreased migration and decreased lymph node metastasis following orthotopic implantation of into nude mice. In human specimens, Yes expression was increased in lymph node metastases relative to paired primary tumors from the same patient, and increased pFAK Y861 expression in lymph node metastases correlated with poor prognosis. These results demonstrate a unique role for Yes in phosphorylation of FAK and in promoting PCa metastasis. Therefore, phosphorylated FAK Y861 and increased Yes expression may be predictive markers for PCa metastasis.
Highlights
Increased migration of cancer cells is a key process in metastasis [1]
As numerous Focal Adhesion Kinase (FAK) activators and downstream signaling molecules are involved in this process, we developed highly migratory sublines of the prostate cancer cell lines PC3 and DU145 by multiple cycles of in vitro selection for cells that had migrated in a modified Boyden chamber
PC3 Mig-3 was increased in migration by 20 fold relative to PC3-P (PC3 parental) cells (Fig. 1B, p < 0.0001); DU145 Mig-3 cells were increased in migration by 6 fold (Fig. 1B) relative to DU145-P (DU145 parental) cells (p < 0.0001)
Summary
Alterations in the expression of numerous gene products through genetic and epigenetic changes have been shown to affect prostate cancer (PCa) cell migration Many of these changes converge on extracellular matrix/tumor interactions that lead www.impactjournals.com/oncotarget to signaling through Focal Adhesion Kinase (FAK), a central mediator of growth regulatory functions [2,3,4]. FAK has been shown to regulate cell survival, proliferation, angiogenesis, epithelial-to-mesenchymal transition, migration, and invasion [9,10,11,12,13,14,15], processes important in tumor progression and metastasis These diverse biologic functions are mediated through the intrinsic FAK tyrosine kinase activity, as well as its role as a scaffolding protein [8, 16]. As FAK inhibitors have reached clinical trials [10], understanding the mechanisms by which FAK signaling pathways are activated and how FAK contributes to PCa progression and metastasis is of important clinical relevance
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