Targeting neuroendocrine differentiation for prostate cancer radiosensitization
Technical Report,30 Sep 2013,29 Sep 2017
Purdue University West Lafayette United States
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Radiotherapy RT is an important primary treatment for low-risk prostate cancer and the standard treatment for high-risk prostate cancer when combined with hormone therapy. Despite that many patients can be cured by RT, several studies suggest that approximately 30-60 of patients with high-risk cancer experience biochemical recurrence within five years after RT, among them 20 of patients die in 10 years. Neuroendocrine differentiation NED is a process by which prostate cancer cells transdifferentiate into neuroendocrine-like NE-like cells, and NED is associated with disease progression and treatment failure. Based on our finding that the transcription factor cAMP response element CREB is responsible for fractionated ionizing radiation FIR-induced NED, we hypothesized that targeting neuroendocrine differentiation can sensitize prostate cancer cells to radiation. During the period of this grant support, we have made the following important discoveries. First, we have demonstrated that FIR-induced NED constitutes two distinct phases acquisition of radiation resistance during the first two weeks and NED during the second two weeks. Further, we have demonstrated that targeting either phase can sensitize prostate cancer cells to radiation, and targeting both phases is a potent radiation sensitization approach. Second, we have identified PRMT5 as a critical upstream regulator of FIR-induced CREB activation and NED. Similarly, targeting PRMT5 during either of the two phases can sensitize prostate cancer cells to radiation. Third, we have discovered that PRMT5 is a novel epigenetic activator of AR transcription in prostate cancer cells and PRMTT5 expression correlates positively with AR expression in prostate cancer tissues. Fourth, we have generated preliminary data showing that PRMT5 may act as a master epigenetic regulator of IR-induced DNA DSBs.
- Medicine and Medical Research