The TLK1-MK5 axis regulates motility, invasion, and metastasis of prostate cancer cells

Abstract

Background: Metastatic dissemination of prostate cancer (PCa) accounts for majority of PCa related deaths. However, the exact mechanism of PCa cell spread is still unknown. We uncovered a novel interaction between two unrelated promotility factors, tousled-like kinase 1 (TLK1) and MAPK-activated protein kinase 5 (MK5), which initiates a signaling cascade promoting metastasis. In PCa, TLK1-MK5 signaling might be crucial as androgen deprivation therapy (ADT) leads to increased expression of both TLK1 and MK5 in metastatic patients, but in this work, we directly investigated the motility, invasive, and metastatic capacity of PCa cells following impairment of the TLK1>MK5 axis. Results: We conducted scratch wound repair and 3D invasion assays with LNCaP and PC3 cells to determine if TLK1 and MK5 can regulate motility and invasion. Both genetic depletion and pharmacologic inhibition of TLK1 and MK5 resulted in reduced migration and invasion through a Matrigel plug. We further elucidated the potential mechanisms underlying these effects and found that that this is likely due to reorganization of the actin fibers at lamellipodia and the focal adhesions network, in conjunction with increased expression of some MMPs that can affect penetration through the ECM. PC3, a highly metastatic cell line when assayed in xenografts, was further tested in tail-vein injection/lung metastasis model, and we showed that following inoculation, treatment with GLPG (MK5 specific inhibitor) or J54 (TLK1 inhibitor) the resulting lung tumor nodules were greatly diminished in number, and for J54 also in size. Conclusion: Our data support that TLK1-MK5 axis is functionally involved in driving PCa cell metastasis and clinical aggressiveness, hence, disruption of this axis may inhibit the metastatic capacity of PCa.