Interplay of CREB and ATF2 in Ionizing Radiation-Induced Neuroendocrine Differentiation of Prostate Cancer Cells
Annual rept. 1 Jun 2008-31 May 2009
PURDUE UNIV LAFAYETTE IN
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Radiation therapy is a first line treatment for prostate cancer patients and the patients 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 Gyday, 5 daysweek, 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.
- Medicine and Medical Research