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

Publisher: Hindawi Pub. Co Country of Publication: United States NLM ID: 101600173 Publication Model: eCollection Cited Medium: Internet ISSN: 2314-6141 (Electronic) NLM ISO Abbreviation: Biomed Res Int Subsets: MEDLINE

Original Publication: New York, NY : Hindawi Pub. Co.

Apoptosis/*physiology ; Class Ia Phosphatidylinositol 3-Kinase/*metabolism ; MicroRNAs/*metabolism ; Prostatic Neoplasms/*metabolism ; Suppressor of Cytokine Signaling 3 Protein/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/*metabolism; Cell Line, Tumor ; Cell Proliferation ; Class Ia Phosphatidylinositol 3-Kinase/genetics ; Humans ; Male ; MicroRNAs/genetics ; Polymerase Chain Reaction ; Suppressor of Cytokine Signaling 3 Protein/genetics ; TNF-Related Apoptosis-Inducing Ligand/genetics

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.
Competing Interests: The authors declare that they have no conflicts of interest.
(Copyright © 2019 Markus Krebs et al.)

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0 (MIRN221 microRNA, human)
0 (MicroRNAs)
0 (SOCS3 protein, human)
0 (Suppressor of Cytokine Signaling 3 Protein)
0 (TNF-Related Apoptosis-Inducing Ligand)
0 (TNFSF10 protein, human)
EC 2.7.1.- (PIK3R1 protein, human)
EC 2.7.1.137 (Class Ia Phosphatidylinositol 3-Kinase)

Date Created: 20191213 Date Completed: 20200427 Latest Revision: 20200427

20240105

PMC6881584

10.1155/2019/6392748

31828111