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

Ximena M. Muresan, Eva Slabáková, Jiřina Procházková, Stanislav Drápela, Radek Fedr, Markéta Pícková, Ondřej Vacek, Ráchel Víchová, Tereza Suchánková, Jan Bouchal, Daniela Kürfürstová, Milan Král, Tereza Hulínová, Radek P. Sýkora, Vladimír Študent, Václav Hejret, Wytske M. van Weerden, Martin Puhr, Václav Pustka, David PotěšilZbyněk Zdráhal, Zoran Culig, Karel Souček*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)1321-1335
Number of pages15
JournalThe American journal of pathology
Issue number9
Publication statusPublished - 1 Sep 2022

Bibliographical note

Funding Information:
Supported by the Czech Ministry of Health grant 17-28518A (Z.C. and K.S.) , DRO-FNOL , 00098892 , and FNOs/2020 (J.B.) ; the European Regional Development Fund ; MEYS CR-CZ.02.1.01/0.0/0.0/16_019/0000868 —Enoch (J.B.); project Preclinical Progression of New Organic Compounds with Targeted Biological Activity (Preclinprogress; K.S.) CZ.02.1.01/0.0/0.0/16_025/0007381 and CEITEC 2020 (LQ1601); and CIISB research infrastructure project LM2018127 and CZ.02.1.01/0.0/0.0/18_046/0015974 (Z.Z.) .

Publisher Copyright:
© 2022 American Society for Investigative Pathology


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