# Targeting PRMT5 enhances the radiosensitivity of tumor cells grown in vitro and in vivo

## TL;DR

This study shows that inhibiting PRMT5 makes tumor cells more sensitive to radiation, both in lab settings and in animal models.

## Contribution

The study demonstrates that PRMT5 inhibition selectively enhances radiosensitivity in tumor cells without affecting normal cells.

## Key findings

- PRMT5 knockdown or inhibition with LLY-283 increased radiosensitivity in multiple tumor cell lines.
- PRMT5 inhibition impaired DNA double-strand break repair in tumor cells.
- LLY-283 treatment enhanced radiation-induced tumor growth delay in mouse xenograft models.

## Abstract

PRMT5 is a widely expressed arginine methyltransferase that regulates processes involved in tumor cell proliferation and survival. In the study described here, we investigated whether PRMT5 provides a target for tumor radiosensitization. Knockdown of PRMT5 using siRNA enhanced the radiosensitivity of a panel of cell lines corresponding to tumor types typically treated with radiotherapy. To extend these studies to an experimental therapeutic setting, the PRMT5 inhibitor LLY-283 was used. Exposure of the tumor cell lines to LLY-283 decreased PRMT5 activity and enhanced their radiosensitivity. This increase in radiosensitivity was accompanied by an inhibition of DNA double-strand break repair as determined by γH2AX foci and neutral comet analyses. For a normal fibroblast cell line, although LLY-283 reduced PRMT5 activity, it had no effect on their radiosensitivity. Transcriptome analysis of U251 cells showed that LLY-283 treatment reduced the expression of genes and altered the mRNA splicing pattern of genes involved in the DNA damage response. Subcutaneous xenografts were then used to evaluate the in vivo response to LLY-283 and radiation. Treatment of mice with LLY-283 decreased tumor PRMT5 activity and significantly enhanced the radiation-induced growth delay. These results suggest that PRMT5 is a tumor selective target for radiosensitization.