Combined microRNA-141 Rescue and MAPK1 Silencing as Putative Strategy to Support Chemotherapy in Translational Stage towards Metastatic Castration-resistant Prostate Cancer – an In Vitro Model Study

Abstract

Tumourigenesis is associated with disruption of cell differentiation, proliferation, migration, and abnormal DNA methylation. Deregulation of transcription factors MAPK1 and NF-κB and other post modification factors play an important role in these processes. Using AR-positive and AR-negative cell line models (LNCaP-p53+/+ and PC3-p53-/-), we found MAPK1 siRNA silencing as potentially productive approach to decrease castration-resistant cell line invasiveness, but not sufficient to abrogate anti-apoptotic, pro-inflammatory by NF-κB signalling, and so we combined this approach with miR-141 rescue (mimic) and inhibition to further modulate autophagy signalling and eventually block MAPK1/NF-κB/ROS pathways. We found miR-141 rescue to upregulate AR and NF-κB inductor ACT1 and to promote total DNA demethylation, in LNCaP, but not in PC3 cells, suggesting microRNA-141 rescue as putative enhancer to MAPK1 blockade in conjunction to pro-apoptotic chemotherapy, but only in transitional towards castration-resistance stages.