Journal Article

miR-221 Augments TRAIL-Mediated Apoptosis in Prostate Cancer Cells by Inducing Endogenous TRAIL Expression and Targeting the Functional Repressors SOCS3 and PIK3R1

Zoni, Eugenio, Kübler, Hubert, Sokolakis, Ioannis, Kneitz, Burkhard, Kalogirou, Charis, Rech, Anne, Schilling, Bastian, Spahn, Martin, Behrmann, Christoph, Krebs, Markus, Kruithof-de Julio, Marianna, Kneitz, Susanne

2019

Overview

miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent.

• Publisher: Hindawi Publishing Corporation,Hindawi,John Wiley & Sons, Inc
• Subject: AKT protein / Antisense RNA / Apoptosis / Apoptosis - physiology / Binding sites / Biological response modifiers / Cell Line, Tumor / Cell Proliferation / Class Ia Phosphatidylinositol 3-Kinase - genetics / Class Ia Phosphatidylinositol 3-Kinase - metabolism / Experiments / Gene expression / Genes / Genetic research / Humans / Interferon / Kinases / Liver cancer / Male / Medical prognosis / Medical research / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / Polymerase Chain Reaction / Prostate cancer / Prostatic Neoplasms - metabolism / Proteins / Repressors / siRNA / Suppressor of Cytokine Signaling 3 Protein - genetics / Suppressor of Cytokine Signaling 3 Protein - metabolism / TNF-Related Apoptosis-Inducing Ligand - genetics / TNF-Related Apoptosis-Inducing Ligand - metabolism / Tumors / Western blotting