Targeting PRMT5 as a Novel Radiosensitization Approach for Primary and Recurrent Prostate Cancer Treatment

Prostate cancer is the second leading cause of cancer death in the United States. Although radiotherapy (RT) is one of the two curative treatments for prostate cancer patients, approximately 10% of low-risk cancer patients and 30-60% of high-risk prostate cancer patients experience biochemical recurrence within five years, among them 20% die in 10 years. The proposed research is based on the hypothesis that targeting protein arginine methyltransferase 5 (PRMT5) can sensitize primary and recurrent prostate cancer cells to RT. During the third grant period, we generated stable cell liens to inducibly express PRMT5 shRNA using DU-145 cells. These stable cell lines will be used to conduct proposed in vivo experiments. As we previously found that inhibition of PRMT5 by a specific inhibitor BLL3.3 did not sensitize radiation-resistant sublines to several chemotherapeutic agents, we tested whether inhibition of PRMT5 can sensitize these cells to ionizing radiation. While BLL3.3 did sensitize parental LNCaP and DU-145 cells to ionizing radiation, inhibition of PRMT5 did not sensitize radiation-resistant cells to radiation. These results collectively suggest that PRMT5 may not be involved in radioresistance in these radiation-resistant cells. Therefore, future search for additional mechanisms is warranted. Continuing previous analysis of PRMT5 expression in prostate cancer tissues, we have also found that PRMT5 expression correlates with AR expression at both mRNA and protein levels. This is very significant given our novel finding that PRMT5 epigenetically regulates AR transcription. In support of this, we have gained additional mechanistic insight that the transcription factor SP1 may recruit PRMT5 to the AR promoter through ChIP studies. The original document contains color images.