Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression.
Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression.
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DOI：
10.1158/0008-5472.can-08-2229
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Hu CD
中科院分区：
文献类型：
--
作者：
Deng X;Liu H;Huang J;Cheng L;Keller ET;Parsons SJ;Hu CD
放射治疗是患有局限性肿瘤的前列腺癌患者的一线治疗。尽管一些患者对治疗反应良好，但大约 10% 的低风险前列腺癌患者和高达 60% 的高风险前列腺癌患者会出现肿瘤复发。然而，肿瘤复发的分子机制仍然很大程度上未知。在这里，我们表明，分段电离辐射 (IR) 诱导 LNCaP 前列腺癌细胞分化为神经内分泌 (NE) 样细胞，已知这些细胞与前列腺癌进展、雄激素非依赖性生长和不良预后有关。进一步的分析表明，两种 CRE 结合转录因子 CREB 和 ATF2 分别作为 NE 样分化的转录激活因子和抑制因子发挥作用，并且 IR 通过增加磷酸化 CREB 的核含量和 ATF2 的细胞质积累来诱导 NE 样分化。与这一概念一致，LNCaP 细胞中不可磷酸化的 CREB 或组成性核定位 ATF2 的稳定表达会抑制 IR 诱导的 NE 样分化。 IR诱导的NE样形态是可逆的，从去分化细胞中分离出的三个IR抗性克隆已经获得了增殖能力并失去了NE样细胞特性。此外，这三个 IR 抗性克隆对 IR 和雄激素耗竭诱导的 NE 样分化表现出不同的反应。然而，它们都对IR和化疗药物多西紫杉醇诱导的细胞死亡以及雄激素消耗诱导的生长抑制具有抵抗力。这些结果表明，放射治疗诱导的 NE 样分化可能代表了前列腺癌细胞在治疗后存活并导致肿瘤复发的新途径。
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 CRE-binding transcription factors, CREB and ATF2, function as a transcriptional activator and 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 non-phosphorylatable 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. Also, these three IR-resistant clones exhibit differential responses to IR- and androgen depletion-induced NE-like differentiation. However, they are all resistant to IR-and the chemotherapeutic agent docetaxel-induced cell death, 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.