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Radiation therapy is a first-line treatment for prostate cancer patients with localized tumors. Although some patients respond well to the treatment, approximately 10% of low-risk and up to 60% of high-risk prostate cancer patients experience recurrent tumors. However, the molecular mechanisms underlying tumor recurrence remain largely unknown. Here we show that fractionated ionizing radiation (IR) induces differentiation of LNCaP prostate cancer cells into neuroendocrine (NE)-like cells, which are known to be implicated in prostate cancer progression, androgen-independent growth, and poor prognosis. Further analyses revealed that two cyclic AMP-responsive element binding transcription factors, cyclic AMP-response element binding protein (CREB) and activating transcription factor 2 (ATF2), function as a transcriptional activator and a repressor, respectively, of NE-like differentiation and that IR induces NE-like differentiation by increasing the nuclear content of phospho-CREB and cytoplasmic accumulation of ATF2. Consistent with this notion, stable expression of a nonphosphorylatable CREB or a constitutively nuclear-localized ATF2 in LNCaP cells inhibits IR-induced NE-like differentiation. IR-induced NE-like morphologies are reversible, and three IR-resistant clones isolated from dedifferentiated cells have acquired the ability to proliferate and lost the NE-like cell properties. In addition, these three IR-resistant clones exhibit differential responses to IR- and androgen depletion-induced NE-like differentiation. However, they are all resistant to cell death induced by IR and the chemotherapeutic agent docetaxel and to androgen depletion-induced growth inhibition. These results suggest that radiation therapy-induced NE-like differentiation may represent a novel pathway by which prostate cancer cells survive the treatment and contribute to tumor recurrence.

Ionizing Radiation Induces Prostate Cancer Neuroendocrine Differentiation through Interplay of CREB and ATF2: Implications for Disease Progression