LncRNA-DANCR Promotes Taxol Resistance of Prostate Cancer Cells through Modulating the miR-33b-5p-LDHA Axis.

Abstract

Prostate cancer (PCa) is one of the most common malignancies in men with high death rate worldwide. Paclitaxel (Taxol) is a widely used anticancer agent. Despite recent improvements in clinical application and research, development of drug resistance limits the efficacy of the Taxol-based chemotherapy. Previous studies revealed that the long noncoding RNA DANCR positively regulated progression of prostate cancer. However, the precise roles of DANCR in the Taxol sensitivity of PCa and the underlying molecular mechanisms remain largely unknown. Here, we report that the expressions of DANCR were significantly upregulated and miR-33b-5p were downregulated in prostate tumor specimens and cells as well as the Taxol-resistant prostate cancer cell line (PC3-TXR). Silencing DANCR or overexpressing miR-33b-5p effectively enhanced the Taxol sensitivity of PCa cells. Bioinformatics analysis, RNA pull-down assay, and luciferase assay consistently illustrated that DANCR was associated with miR-33b-5p, leading to downregulation of miR-33b-5p in PCa. Interestingly, glucose metabolism of PC3-TXR cells was remarkedly elevated. The glucose uptake, extracellular acidification rate (ECAR), and glycolysis speed-limiting enzyme expressions were significantly promoted in PC3-TXR cells. We further identified the glucose metabolism enzyme; LDHA was a direct target of miR-33b-5p in PCa cells. LDHA restoration attenuated miR-33b-5p-mediated PTX sensitization. Finally, the rescue of miR-33b-5p in DANCR-overexpressing PC3-TXR cells successfully overrode the DANCR-promoted Taxol resistance. In summary, this study uncovered biological roles and molecular mechanisms of the DANCR-promoted chemoresistance, contributing to the development of noncoding RNA-based therapeutic strategies against drug-resistant prostate cancer.