Targeting Neuroendocrine Differentiation for Prostate Cancer Radiosensitization
Abstract
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 10% of patients with low-risk cancer and up to 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. 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. We proposed two CREB targeting strategies as a model system to test our hypothesis. During the first year of grant support, we have established multiple stable and doxycycline/tetracycline-inducible cell lines that express short hairpin RNAs (shRNAs) to knock down CREB or express ACREB, a dominant negative mutant of CREB. We have examined the effect of ACREB expression on FIR-induced cell death in LNCaP cells, and found that induction of ACREB during the first two weeks (weeks 1-2), the second two weeks (weeks 3-4), or the entire four weeks (weeks 1-4) efficiently increased FIR-induced cell death and inhibited the extent of NED in survival cells. Further, clonogenic assays have also showed that ACREB expression sensitized LNCaP cells to radiation in a dose-dependent manner. In support of this notion, CREB knockdown also sensitized LNCaP cells to radiation in clonogenic assays.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA613326
Entities
People
- Chang-deng Hu
- Gyeon Oh
- Xuehong Deng
Organizations
- Purdue University