Targeting PRMT5 as a Novel Radiosensitization Approach for Primary and Recurrent Prostate Cancer Treatment
Annual rept. 1 Aug 2013-31 Jul 2014
PURDUE UNIV LAFAYETTE IN
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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 second grant period, we completed a pilot study to demonstrate that the stable cell lines established from lentiviral transduction did not show efficient knockdown of PRMT5. As an alternative approach, we have re-established stable cell lines isolated from single cells. These cells will be useful for proposed in vivo experiments. We have also completed the chemosensitization experiments and found that inhibition of PRMT5 did not sensitize LNCaP and DU-145 cells as well as their radioresistant sublines to docetaxel, cisplatin and etoposide. As etoposide is also an inducer of DNA double strand breaks, this result suggests that PRMT5 may utilize a different mechanism to sensitize prostate cancer cells to ionizing radiation. We will further test whether inhibition of PRMT5 can sensitize radioresistant sublines to ionizing radiation. We have also performed immunohistochemical analysis of PRMT5 expression in a prostate cancer tissue microarray and found that PRMT5 is highly expressed in intermediate- and high-risk prostate cancer patients, suggesting that PRMT5 expression may drive the progression of prostate cancer and possibly contribute to radioresistance. In support of this, we have continued to explore the underlying mechanism by which PRMT5 knockdown inhibits prostate cancer cell proliferation.
- Medicine and Medical Research