Targeting PRMT5 enhances the radiosensitivity of tumor cells grown in vitro and in vivo
PRMT5 is a broadly expressed arginine methyltransferase that plays a crucial role in tumor cell proliferation and survival. This study explored whether PRMT5 could be targeted to enhance the effectiveness of radiotherapy. We found that silencing PRMT5 with siRNA increased the radiosensitivity of various tumor cell lines commonly treated with radiation. To investigate this further, we used the PRMT5 inhibitor LLY-283 in experimental settings. LLY-283 treatment reduced PRMT5 activity in tumor cells and further increased their sensitivity to radiation. This heightened radiosensitivity was associated with impaired DNA double-strand break repair, as evidenced by γH2AX foci and neutral comet assays.
In contrast, normal fibroblasts showed no change in radiosensitivity despite reduced PRMT5 activity following LLY-283 treatment. Transcriptome analysis of U251 cells revealed that LLY-283 not only decreased the expression of genes involved in the DNA damage response but also altered their mRNA splicing patterns. In vivo experiments using subcutaneous xenografts demonstrated that LLY-283 treatment lowered PRMT5 activity in tumors and significantly improved radiation-induced growth delay. These findings indicate that PRMT5 could serve as a selective target for radiosensitization in cancer therapy.