Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Krebs M

PROVIDER: S-EPMC6881584 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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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 Markus M Behrmann Christoph C Kalogirou Charis C Sokolakis Ioannis I Kneitz Susanne S Kruithof-de Julio Marianna M Zoni Eugenio E Rech Anne A Schilling Bastian B Kübler Hubert H Spahn Martin M Kneitz Burkhard B

BioMed research international 20191114

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 apop ...[more]

PMID: 31828111

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Project description:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be a potent inducer of apoptosis in various cancer cell lines and primary cancer cells. However, in clinical trials administration of recombinant TRAIL or TRAIL death receptor agonists did not show sufficient efficacy for treatment of tested malignant disorders compared to standard chemotherapy. Acquired resistance of cancer cells to TRAIL and to other âdeath receptorâ ligands may explain not only the inability of TRAIL and TRAIL âdeath receptorâ agonists to achieve the clearance of cancer cells in vivo but also the escape of cancer cells from immune cell â mediated killing. Selective pressure of TRAIL on TRAIL-sensitive Jurkat T-lymphoblastic leukemia cells provided several TRAIL resistant Jurkat cell line clones (TR1, TR2, TR3). We showed that acquired TRAIL resistance was associated with complex disruption of both extrinsic and intrinsic apoptotic pathways manifested by acquired multi-drug resistant phenotype of TR1, TR2, and TR3 clones. To identify changes associated with TRAIL resistance of Jurkat cells we performed genome-wide gene expression analysis of TRAIL-resistant clones (TR) and compared to WT Jurkat cells. We identified significantly increased expression (1.33-fold change with adjusted p < 0.05) of 73 genes in TR1 clone, 53 genes in TR2 clone and 8 genes in TR3 clone, and significant decrease in expression (0.75-fold change with adjusted p < 0.05) of 174 genes in TR1 clone, 36 genes in TR2 clone and 28 genes in TR3 clone. There was an overlap of only 2 significantly overexpressed (midkine / MDK and zinc finger and BTB domain containing 16 gene / ZBTB16 / PLZF) and 4 downregulated genes (YAP1, IGJ, EIF1AY, RPS4Y1) in all three TR clones. Total cellular RNA was isolated from biologic duplicates of untreated Jurkat cells (WT) and TRAIL resistant Jurkat cell line subclones (TR1, TR2, TR3) established by selective pressure of TRAIL 1000 ng/mL on Jurkat cells over the period of 12 weeks.

Dataset Information

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

Publications

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

Similar Datasets

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