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Toll-Like Receptor 3 Overexpression Induces Invasion of Prostate Cancer Cells, whereas Its Activation Triggers Apoptosis

2022; Elsevier BV; Volume: 192; Issue: 9 Linguagem: Inglês

10.1016/j.ajpath.2022.05.009

1525-2191

Ximena Maria Mureșan, Eva Slabáková, Jiřina Procházková, Stanislav Drápela, Radek Fedr, Markéta Pícková, Ondřej Vacek, Ráchel Víchová, Tereza Suchánková, Jan Bouchal, Daniela Kurfürstová, Milan Král, Tereza Hulínová, Radek Sýkora, Vladimír Študent, Václav Hejret, Wytske M. van Weerden, Martin Puhr, Václav Pustka, David Potěšil, Zbyněk Zdráhal, Zoran Čulig, Karel Souček,

Prostate Cancer Treatment and Research

Toll-like receptor 3 (TLR3) is an endosomal receptor expressed in several immune and epithelial cells. Recent studies have highlighted its expression also in solid tumors, including prostate cancer (PCa), and have described its role primarily in the proinflammatory response and induction of apoptosis. It is up-regulated in some castration-resistant prostate cancers. However, the role of TLR3 in prostate cancer progression remains largely unknown. The current study experimentally demonstrated that exogenous TLR3 activation in PCa cell lines leads to a significant induction of secretion of the cytokines IL-6, IL-8, and interferon-β, depending on the model and chemoresistance status. Transcriptomic analysis of TLR3-overexpressing cells revealed a functional program that is enriched for genes involved in the regulation of cell motility, migration, and tumor invasiveness. Increased motility, migration, and invasion in TLR3-overexpressing cell line were confirmed by several in vitro assays and using an orthotopic prostate xenograft model in vivo. Furthermore, TLR3-ligand induced apoptosis via cleavage of caspase-3/7 and poly (ADP-ribose) polymerase, predominantly in TLR3-overexpressing cells. These results indicate that TLR3 may be involved in prostate cancer progression and metastasis; however, it might also represent an Achilles heel of PCa, which can be exploited for targeted therapy.