Interplay of CREB and ATF2 in Ionizing Radiation-Induced Neuroendocrine Differentiation of Prostate Cancer Cells
Abstract
Radiation therapy is a first line treatment for prostate cancer patients and the patient's response is generally good. However, approximately 10% of low grade and up to 60% of high grade of patients will experience tumor recurrence. We have found that following a clinical radiation therapy protocol (2 Gy/day, 5 days/week), ionizing radiation (IR) induced the LNCaP prostate cancer cells to transdifferentiate into neuroendocrine-like (NE-like) cells, a process also known as neuroendocrine differentiation (NED) that is associated with disease progression and the acquisition of androgen-independent growth. Once differentiated, the NE-like cells are highly resistant to radiation and survive the treatment without any obvious cell death. Furthermore, we have demonstrated that two transcription factors, CREB and ATF2 that can bind the same DNA sequence for gene transcription, are involved in this process. Irradiated cells accumulate a large amount of ATF2 in the cytoplasm concurrent with an increased amount of phosphorylated form of CREB (pCREB) in the nucleus. Further evidence suggests that ATF2 acts as a transcriptional repressor and CREB functions as a transcriptional activator in NED. Significantly, we also found that IR-induced NE-like cells are reversible and dedifferentiated cells are cross-resistant to radiation, androgen ablation and chemotherapeutic agent docetaxel treatments. These findings suggest that radiation-induced NED may represent a novel pathway by which prostate cancer cells survive the treatment and contribute to recurrence.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 30, 2009
- Accession Number
- ADA512026
Entities
People
- Chang-deng Hu
Organizations
- Purdue University