Tetrabenazine-induced miR-34a-5p suppresses the tumorigenicity of radioresistant colorectal cancer by inhibiting M2 macrophage polarization.

[BACKGROUND] Radiotherapy is a very common treatment method for various cancers; however, it is not effective for patients with radioresistance. Accordingly, the discovery of drugs for patients with radioresistance cancer is critical. This study used a Food and Drug Administration (FDA)-approved drug library to identify candidate drugs for the treatment of radioresistant colorectal cancer (CRC). This approach to drug development benefits from its low cost and time requirements and can lead to rapid clinical translation.

[METHODS] Drugs that suppress radioresistance in CRC cells were screened. Effects of candidate drugs on cell viability and the expression of epithelial-mesenchymal transition (EMT)-related factors were evaluated through using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and quantitative real-time PCR (qRT-PCR). The effects of TBZ, identified as a candidate, on radioresistant CRC cells and organoids were evaluated using MTT, qRT-PCR, western blotting, migration, and invasion assays. Factors mediating the suppressive effects of TBZ on tumorigenicity, including the roles of Snail and the p53-miR-34a-5p axis, were evaluated using chromatin immunoprecipitation (ChIP), promoter luciferase, western blotting, qRT-PCR, and dual luciferase assays. Expression of M2 markers in THP-1-derived macrophages was confirmed by qRT-PCR.

[RESULTS] TBZ, an anti-hyperkinesia drug, was identified as a candidate agent able to reduce tumorigenicity. In radioresistant CRC cells, treatment with TBZ downregulated EMT-related factors and decreased cell migratory ability and invasiveness via reductions in Snail expression through p53-induced miR-34a-5p. Cell migration and invasion assays confirmed that TBZ had greater inhibitory effects on the migration and invasiveness of radioresistant CRC cells than those of 5-FU. Furthermore, TBZ-induced miR-34a-5p reduced M2 macrophage polarization and IL-10 secretion, thereby reducing the tumorigenicity of radioresistant CRC cells. These findings were verified using samples from patients with CRC.

[CONCLUSIONS] TBZ reduces tumorigenicity via the regulation of the p53-miR-34a-5p/Snail axis in radioresistant CRC cells and suppression of M2 macrophage polarization, decreasing IL-10 secretion. Our study provides insight into drug repurposing by revealing the mechanism by which TBZ, an FDA-approved drug, reduces tumorigenicity through communication between radioresistant CRC cells and macrophages.