关键词：电离辐射；前列腺癌；放射疗法
摘 要：Prostate cancer is the second leading cause of cancer death among American men. 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 first grant period, we have successfully demonstrated that knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor can sensitize prostate cancer cells (LNCaP, DU-145 and PC-3) to radiation in vitro. This radiosensitization is likely due to the involvement of PRMT5 in the regulation of the DNA damage response. These results collectively suggest that targeting PRMT5 can sensitize prostate cancer cells to radiation. We are currently isolating stably integrated clones to inducibly knock down PRMT5 for proposed in vivo experiments. We have also successfully isolated 3 radiation-resistant sublines from DU-145 after 40 Gy of fractionated ionizing radiation. These resistant cell sublines along with previously isolated LNCaP radiation- resistant sublines will be used for PRMT5 targeting experiments. In addition, we found that PRMT5 regulates prostate cancer cell growth in an AR-dependent manner, and this effect is likely medicated by epigenetic regulation of AR transcription. We will continue to pursue this novel and exciting finding.