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

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.

Automated summary

This study reveals the role of DANCR in taxol resistance and the underlying molecular mechanisms. The study found that DANCR was upregulated and miR-33b-5p was downregulated in prostate tumor specimens and taxol-resistant prostate cancer cells. Silencing DANCR or overexpressing miR-33b-5p enhanced the taxol sensitivity of prostate cancer cells. The study also identified an association between DANCR and miR-33b-5p, leading to downregulation of miR-33b-5p in prostate cancer. The study further showed that glucose metabolism was elevated in taxol-resistant prostate cancer cells, and LDHA was a direct target of miR-33b-5p. Restoring miR-33b-5p successfully overcame the DANCR-promoted taxol resistance.