miR-17-3p Downregulates Mitochondrial Antioxidant Enzymes and Enhances the Radiosensitivity of Prostate Cancer Cells

Radioresistance remains to be a major obstacle in the management of patients with advanced prostate cancer (PCa). We have identified a mature miR-17-3p processed from the 3′ arm of precursor miR-17, which appeared to be able to inhibit three major antioxidant enzymes located in mitochondria, i.e., m...

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Bibliographic Details
Published in:Molecular therapy. Nucleic acids 2018-12, Vol.13, p.64-77
Main Authors: Xu, Zhi, Zhang, Yanyan, Ding, Jiaji, Hu, Weizi, Tan, Chunli, Wang, Mei, Tang, Jinhai, Xu, Yong
Format: Article
Language:English
Subjects:
Androgens
antioxidant enzymes
Antioxidants
Apoptosis
Cancer therapies
Cytotoxicity
Deoxyribonucleic acid
DNA
Enzymes
Experiments
Glutathione peroxidase
Ionizing radiation
Manganese
MicroRNAs
miR-17-3p
miRNA
Mitochondria
Prostate cancer
Proteins
R&D
Radiation therapy
Radioresistance
Radiosensitivity
Reactive oxygen species
Reductase
Research & development
Respiration
Superoxide dismutase
Thioredoxin
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Summary:Radioresistance remains to be a major obstacle in the management of patients with advanced prostate cancer (PCa). We have identified a mature miR-17-3p processed from the 3′ arm of precursor miR-17, which appeared to be able to inhibit three major antioxidant enzymes located in mitochondria, i.e., manganese superoxide dismutase (MnSOD), glutathione peroxidase 2 (Gpx2), and thioredoxin reductase 2 (TrxR2). Here we show that upregulation of miR-17-3p remarkably sensitized PCa cells to ionizing radiation (IR). Reductions of the three antioxidants led to increasing cellular reactive oxygen species (ROS) accumulation as well as declining mitochondrial respiration. The miR-17-3p-mediated dysfunction of mitochondrial antioxidants apparently sensitizing IR therapy was manifested in vitro and in vivo. Substantially, the miR-17-3p effect on suppression of the antioxidants can be efficiently eliminated or attenuated by transfecting with either an miR-17-3p inhibitor or each of the related antioxidant cDNA expression constructs. Overall, in addition to the insights into the functional assessments for the duplex of miR-17-5p and miR-17-3p, the present study highlights the rigorous evidence that demonstrated suppression of multiple mitochondrial antioxidants by a single microRNA (miRNA), thereby providing a promising approach to improve radiotherapy for advanced PCa by targeting mitochondrial function.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2018.08.009