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

• Main Authors: Zhi Xu, Yanyan Zhang, Jiaji Ding, Weizi Hu, Chunli Tan, Mei Wang, Jinhai Tang, Yong Xu
• Format: Article
• Language: English
• Published: Elsevier 2018-12-01
• Series: Molecular Therapy: Nucleic Acids
• Online Access: http://www.sciencedirect.com/science/article/pii/S216225311830221X

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. Keywords: miR-17-3p, antioxidant enzymes, reactive oxygen species, radiosensitivity, prostate cancer