Interplay of CREB and ATF2 in Ionizing Radiation-Induced Neuroendocrine Differentiation of Prostate Cancer Cells.

摘要

Radiation therapy is a first line treatment for prostate cancer patients and the patient's response is generally good. However, approximately 10% of low-risk and up to 60% of high-risk prostate cancer patients will experience biochemical recurrence within five years after radiotherapy. 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 oppose each other to regulate IR- induced NED. Significantly, we also found that IR-induced NE-like cells are reversible and dedifferentiated cells are cross-resistant to treatments. We have also extended our findings in LNCaP cells to two other prostate cancer cell lines and demonstrated that targeting CREB signaling can increase IR- induced cell death. We also demonstrated that IR induces NED in xenograft nude mouse models and in human prostate cancer patients. Preliminary screening has identified CaMKII and PRMT5 as important regulators of CREB involved in IR- induced NED. These findings suggest that radiation-induced NED may represent a novel pathway by which prostate cancer cells survive the treatment and contribute to recurrence.