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

  • Krebs M Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.
  • Behrmann C Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.
  • Kalogirou C Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.
  • Sokolakis I Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.
  • Kneitz S Physiological Chemistry, University of Würzburg, Biocentre, Würzburg, Germany.
  • Kruithof-de Julio M Urology Research Laboratory, Department of Biomedical Research, University of Bern, Bern, Switzerland.
  • Zoni E Urology Research Laboratory, Department of Biomedical Research, University of Bern, Bern, Switzerland.
  • Rech A Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
  • Schilling B Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
  • Kübler H Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.
  • Spahn M Urology Hirslanden Zürich, Zürich, Switzerland.
  • Kneitz B Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.
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  • 2019-12-13
Published in:
  • BioMed research international. - 2019
Apoptosis
Cell Line, Tumor
Cell Proliferation
Class Ia Phosphatidylinositol 3-Kinase
Humans
Male
MicroRNAs
Polymerase Chain Reaction
Prostatic Neoplasms
Suppressor of Cytokine Signaling 3 Protein
TNF-Related Apoptosis-Inducing Ligand
English 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.
Language
  • English
Open access status
gold
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https://sonar.ch/global/documents/385
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